Clinical trial NCT01595529
Conditions: Urinary Tract Infection
Keywords: antibiotic therapy antimicrobial resistance children E.coli K.pneumoniae parent study SCOUT Study spectrum stool bacteria stool culture urinary tract infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2012-05-18; Completion date: 2019-08-12
Enrollment: 717 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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:
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.

Arms: arm 1: 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) arm 2: 5 days of placebo treatment to match physician-initiated therapy
Interventions: intervention 1: Cefixime intervention 2: Cephalexin intervention 3: Placebo intervention 4: Trimethoprim/Sulfamethoxazole
Intervention descriptions: intervention 1: Cefixime 8 mg/kg/day orally, in 1 dose, with a maximum of 400 mg. Subjects originally receiving Cefdinir will receive Cefixime. intervention 2: Cephalexin 50mg/kg/day in 3 divided doses intervention 3: Placebo to match the other four active treatments intervention 4: 8 mg/kg/day of Trimethoprim-sulfamethoxazole (TMP-SMX) orally in 2 divided doses, with a maximum dose of 160 mg twice a day.

Protocol documents:
Prot_000.pdf: 
“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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DMID Protocol Number: DMID 09-0103 
DMID Funding Mechanism: Contract No. HHSN272200900022C 
Pharmaceutical Support Provided by: The Investigational Drug Service (IDS) of the 
Institute for Translational Medicine and Therapeutics at the UPENN School of Medicine  
Other Identifying Numbers: MIDRCB-B 
BAA-NIAID-DMID-NIHAI2008025 
Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance 
The SCOUT Study: “Short Course Therapy for Urinary Tract Infections in Children” 
IND Sponsor: DMID 
Principal Investigator: Theoklis Zaoutis, MD, MSCE 
DMID Clinical Project Manager: Maureen Mehigan, RN 
DMID Medical Monitor: Venus Shahamatdar, MD 
Draft Version Number:  13.0 
Version Date: September 20, 2018 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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STATEMENT OF COMPLIANCE 
This study will be conducted in full accordance with all applicable Children’s Hospital of 
Philadelphia and Children’s Hospital of Pittsburgh’s Research Policies and Procedures and all 
applicable Federal and state laws and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 
56, 312, 314 and 812 and the Good Clinical Practice: Consolidated Guideline approved by the 
International Conference on Harmonisation (ICH). Any episode of noncompliance will be 
documented. 
 
The investigators will perform the study in accordance with this IRB-approved protocol, will 
obtain consent and assent, and will report adverse events (AEs) in accordance with Children’s 
Hospital of Philadelphia and Children’s Hospital of Pittsburgh’s IRB Policies and Procedures 
and all federal requirements. The Principal Investigator will assure that no changes to the 
protocol will take place without prior agreement from the sponsor and documented approval 
from the IRB, except where necessary to eliminate an immediate hazard(s) to the study 
participants. The Principal Investigator will promptly report to the IRB and the sponsor any 
changes in research activity and all unanticipated problems involving risk to human subjects, or 
others. Collection, recording, and reporting of data will be accurate and will ensure the privacy, 
health, and welfare of research subjects during and after the study.  
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Investigators: Children's Hospital of Philadelphia (CHOP): Theoklis Zaoutis, MD, MSCE 
                              Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center 
                              (PITT): Alejandro Hoberman, MD 
 
Signed: 
 
 
 
 
Name                                                                                  
 
____________________________________________ 
Title 
 
 
 
             Date 
Signed: 
Name 
 
 
             Date 
 
Title 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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TABLE OF CONTENTS 
 
 
Page 
Statement of Compliance ................................................................................................................ ii 
Signature Page ............................................................................................................................... iii 
Table of Contents ............................................................................................................................ iv 
List of Abbreviations........................................................................................................................ ix 
Protocol Summary ......................................................................................................................... xii 
1 
Key Roles ................................................................................................................................1 
2 
Background Information and Scientific Rationale ..................................................................3 
2.1 
Background Information ..............................................................................................3 
2.2 
Rationale .....................................................................................................................5 
2.3 
Potential Risks and Benefits .......................................................................................7 
2.3.1 
Potential Risks ................................................................................................7 
2.3.2 
Potential Benefits ......................................................................................... 11 
3 
DEFINITIONS ...................................................................................................................... 12 
4 
Objectives ............................................................................................................................ 15 
4.1 
Study Objectives ...................................................................................................... 15 
4.2 
Study Outcome Measures ..........................................................................................1 
4.2.1 Primary and Secondary Outcome Measures ....................................................1 
5 
Study Design ...........................................................................................................................6 
5.1 
Sub-studies .................................................................................................................6 
6 
Study Enrollment and Withdrawal ..........................................................................................9 
6.1  
Subject Inclusion Criteria:  Must Meet All ...................................................................9 
6.2 
Subject Exclusion Criteria: Meets at Least One ...................................................... 10 
6.3 
Recruitment Strategy ............................................................................................... 11 
6.4 
Treatment Assignment Procedures ......................................................................... 11 
6.4.1 
Randomization Procedures ......................................................................... 11 
6.4.2 
Masking Procedures .................................................................................... 12 
6.4.3 
Reasons for Withdrawal ............................................................................... 13 
6.4.4 
Handling of Withdrawals .............................................................................. 14 
6.4.5 
Termination of Study .................................................................................... 14 
7 
Study Intervention/Study product ........................................................................................ 16 
7.1  
Study Product Description ....................................................................................... 16 
7.1.1 
Acquisition .................................................................................................... 17 
7.1.2 
Formulation, Packaging, and Labeling ........................................................ 17 
7.1.3 
Study product Storage ................................................................................. 18 
7.2 
Dosage, Preparation and Administration of Study Intervention/Study product ...... 18 
7.3 
Modification of Study Intervention/Study product for a Participant ......................... 20 
7.4 
Accountability Procedures for the Study Intervention/Study product(s) ................. 20 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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7.5 
Assessment of Subject Compliance with Study Intervention/Study product .......... 21 
7.6 
Concomitant Medications/Treatments ..................................................................... 22 
8 
Study Schedule .................................................................................................................... 23 
8.1 
Recruitment and Preliminary Screening .................................................................. 25 
8.2 
Enrollment Visit (Day 2-6 from start of prescribed antibiotics) ................................ 26 
8.3 
Test of Cure (TOC) Post Treatment Visit ................................................................ 29 
8.4 
Outcome Assessment Visit ...................................................................................... 33 
8.5 
Follow-Up Phone Call .............................................................................................. 33 
Day 38 – 44 (28-34 days after completing the study product): ........................................... 33 
8.6 
Early Termination Visit ............................................................................................. 34 
9 
Study Procedures/Evaluations ............................................................................................ 35 
9.1 
Clinical Evaluations .................................................................................................. 35 
9.2 
Laboratory Evaluations ............................................................................................ 36 
9.2.1 
Clinical Laboratory Evaluations ................................................................... 37 
9.2.2 
Special Assays or Procedures ..................................................................... 39 
9.2.3 
Specimen Preparation, Handling, and Shipping ......................................... 39 
10 
Assessment of Safety .......................................................................................................... 41 
10.1 
Specification of Safety Parameters ......................................................................... 41 
10.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ............................................................................................................... 42 
10.2.1 Adverse Events ............................................................................................ 42 
10.2.2 Serious Adverse Events .............................................................................. 44 
10.2.3 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .......................................................... 45 
10.3 
Reporting Procedures .............................................................................................. 45 
10.3.1 Adverse Events ............................................................................................ 45 
10.3.2 Serious Adverse Events .............................................................................. 45 
10.3.3 Regulatory Reporting for Studies Conducted Under DMID-Sponsored 
IND ............................................................................................................... 47 
10.4 
Type and Duration of Follow-up of Subjects after Adverse Events ........................ 48 
10.5 
Halting Rules ............................................................................................................ 48 
10.6 
Safety Oversight ...................................................................................................... 50 
11 
Clinical Monitoring ................................................................................................................ 51 
11.1 
Site Monitoring Plan ................................................................................................. 51 
12 
Statistical Considerations .................................................................................................... 52 
12.1 
Study Objectives ...................................................................................................... 52 
12.2 
Sample Size Considerations ................................................................................... 53 
12.3 
Planned Interim Analyses ........................................................................................ 54 
12.4 
Final Analysis Plan................................................................................................... 54 
13 
SOURCE Documents and Access to Source Data/Documents ......................................... 61 
14 
Quality Control and Quality Assurance ............................................................................... 62 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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15 
Ethics/Protection of Human Subjects .................................................................................. 63 
15.1 
Ethical Standard ....................................................................................................... 63 
15.2 
Institutional Review Board ....................................................................................... 63 
15.3 
Informed Consent Process ...................................................................................... 63 
15.3.1 Informed Consent/Assent Process (in Case of a Minor) ............................. 65 
15.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 65 
15.5 
Payment to Subjects/Families ................................................................................. 65 
15.6 
Subject Confidentiality ............................................................................................. 65 
15.7 
Future Use of Stored Specimens ............................................................................ 66 
16 
Data Handling and Record Keeping .................................................................................... 68 
16.1 
Data Management Responsibilities ......................................................................... 68 
16.2 
Data Capture Methods ............................................................................................. 69 
16.3 
Types of Data ........................................................................................................... 72 
16.4 
Timing/Reports ......................................................................................................... 72 
16.5 
Study Records Retention ......................................................................................... 73 
16.6 
Protocol Deviations .................................................................................................. 74 
17 
Publication Policy ................................................................................................................. 75 
18 
Literature References .......................................................................................................... 76 
SupplementS/Appendices ............................................................................................................ 82 
APpendix A: Schedule of Events .................................................................................................. 83 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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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 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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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 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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LIST OF ABBREVIATIONS 
C 
Degrees centigrade 
AAP 
American Academy of Pediatrics 
AE 
Adverse Event/Adverse Experience 
APN 
Acute pyelonephritis 
BDMC 
Biostatistics and Data Management Core 
CHOP 
Children’s Hospital of Philadelphia 
CDM 
Clinical Data Manager 
CFR 
Code of Federal Regulations 
CFU/mL 
Colony Forming Units per milliliter 
CLSI 
Clinical Lab and Standards Institute 
CONSORT 
Consolidated Standards of Reporting Trials 
CRA 
Clinical Research Assistant 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTC 
Clinical Trial Center 
CTRC 
Clinical and Translational Research Center 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
DMP 
Data Management Plan 
DMSA 
Dimercaptosuccinic acid 
DSMB 
Data and Safety Monitoring Board  
eCRF 
Electronic Case Report Form 
ED 
Emergency Department  
EHR 
Electronic Health Record 
ESBL 
Extended Spectrum Beta Lactamases 
FDA 
Food and Drug Administration 
FWA 
Federal wide Assurance 
F/SUTI 
Febrile or Symptomatic Urinary Tract Infection 
FUTI 
Febrile Urinary Tract Infection 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive Care Unit 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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IDE 
Investigational Device Exemption 
IDS 
Investigational Drug Service 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IVR 
Interactive Voice Response System 
ITT 
Intention to Treat 
JAMA 
Journal of the American Medical Association 
MedDRA  
Medical Dictionary for Regulatory Activities 
MOA 
Memorandum or Memoranda of Agreement 
MOP 
Manual of Procedures 
MOU 
Memorandum or Memoranda of Understanding 
N 
Number (typically refers to subjects) 
N/A 
Not Applicable 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OC 
Oracle Clinical 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PeRC 
CHOP Pediatric Research Consortium 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PITT 
Children’s Hospital of Pittsburgh 
PITTnet 
PITT Practice Based Research Network 
PK 
Pharmacokinetics 
PKU 
Phenylketonuria 
PMO 
Program Management Office 
QA 
Quality Assurance 
QC 
Quality Control 
RDC 
Remote Data Capture 
RIS 
Research Information Systems 
RNA 
Ribonucleic acid  
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SCOUT 
Short COurse Therapy for Urinary Tract Infections in Children 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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SP 
Special Publication 
SUTI 
Symptomatic Non-febrile Urinary Tract Infection 
TOC 
Test of Cure 
TBD 
To Be Determined/Developed 
TCP/IP 
Transport Control Protocol / Internet Protocol 
TMP-SMX 
Trimethoprim-Sulfamethoxazole  
UA 
Urinalysis 
UPENN 
University of Pennsylvania 
UPS 
United Parcel Service of America 
UTI 
Urinary Tract Infection 
VUR 
Vesicoureteral reflux 
WARP 
Westat Automated Report Portal 
WBC/hpf 
White Blood Cells per High Powered Field 
WBC/mm^3 
White Blood Cell per cubic millimeter 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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PROTOCOL SUMMARY 
Title: 
 
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 of 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). 
Phase: 
Phase II 
Population: 
 
Children: ages two months (at least 36 weeks gestational age from 
birth for subjects < two years of age) to 10 years with a confirmed 
urinary tract infection (UTI) diagnosis treated by one of four antibiotics 
(trimethoprim-sulfamethoxazole (TMP-SMX) or cefixime or cefdinir or 
cephalexin). The SCOUT Study will only enroll those children with 
documented clinical improvement (afebrile and asymptomatic) after 
initiation of antibiotic treatment. Subjects can be enrolled at any time 
after they initiate their originally prescribed antibiotic treatment, 
providing they meet all inclusion/exclusion criteria.  However, all 
subjects will remain on their originally prescribed antibiotic treatment 
through the end of Day 5.  Subjects will initiate their SCOUT study 
product beginning on Day 6.  Subjects may be enrolled on Day 6 
providing they have not started the Day 6 of their originally prescribed 
antibiotic treatment.  Enrolled subjects that develop a fever or have 
worsening symptoms prior to taking the first dose of SCOUT therapy 
on Day 6 will be considered entry failures and withdrawn from the 
study. 
 
A urinary tract infection (UTI) will be defined as the presence (in the 
medical record or by parent report) of:  
(1) At least one of the symptoms consistent with the diagnosis of UTI 
including: 
• 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 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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• 
vomiting 
             AND 
(2) Pyuria based on urinalysis; 
•  >10 WBC/mm3 (uncentrifuged specimen) OR 
•  >5 WBC/hpf (centrifuged specimen), OR 
• Leukocyte esterase > trace on dipstick. 
             AND  
(3) Culture-proven infection with a single  uropathogen: 
• > 5 x 104 CFU/mL (catheterized or suprapubic aspiration urine 
specimen) OR 
   • > 105 CFU/mL (clean void specimen) 
Number of Sites: 
There are two participating clinical trial centers (CTCs): Children’s 
Hospital of Philadelphia (CHOP) and Children’s Hospital of Pittsburgh 
(PITT). Children will be recruited in the primary and urgent care offices, 
emergency departments, and hospital wards from both CTCs. 
Study Design: 
 
 
 
 
 
 
 
 
 
Study Duration: 
 
The SCOUT Study is a multi-center, centrally randomized, double-
blind, placebo-controlled non-inferiority clinical trial. The study will 
enroll about 746 children ages two months (at least 36 weeks 
gestational age for subjects < two years of age) to 10 years to evaluate 
672 for the study’s primary outcome measure.  Enrolled subjects will 
be stratified based on presence of fever (a temperature of at least 
100.4°F or 38°C measured anywhere on the body) at the initial 
presentation of UTI symptoms and by specific antibiotic therapy 
prescribed by the original treating clinician. At time of enrollment, 
children will be blindly randomized to the standard course of 
antimicrobial therapy arm (continue on antibiotics from Day 6-Day 10) 
or the short course antimicrobial therapy arm (receive placebo from 
Day 6-Day 10).  Parents of subjects enrolled prior to completion of Day 
5 of the original prescribed antibiotic prescription will be instructed to 
complete the prescribed treatment through the end of Day 5, and 
initiate SCOUT study therapy beginning on Day 6.  Parents of subjects 
enrolled prior to Day 5 will be contacted by SCOUT study staff on Day 
5 or Day 6 (prior to taking first dose of SCOUT study treatment on Day 
6) to verify that the subjects do not have a fever or worsening of 
symptoms.   
Subjects will be enrolled over approximately a four and a half year 
period.   
Subject Participation 
Duration: 
The study period will begin on Day 6 after initial antibiotic therapy (Day 
1 of SCOUT-directed treatment) is started and extend until the final 
follow-up phone call (four weeks after completing the study product 
therapy). Study duration for each individual subject will be 
approximately five weeks.   


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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Description of Agent or 
Intervention: 
 
The SCOUT Study will enroll children whose prescribing clinician 
initiated therapy with one of four antibiotics (trimethoprim-
sulfamethoxazole sulfamethoxazole (TMP-SMX) or cefixime or cefdinir 
or cephalexin) for UTI in children across the two participating clinical 
sites.  On occasion cefixime may not be available to the prescribing 
primary care physician.  Under such circumstances it is likely that 
cefdinir will be prescribed as an alternative agent to cefixime instead. 
The two antibiotics have therapeutic equivalence. If a child initially 
prescribed cefdinir is enrolled, they will be randomized to either five 
additional days of cefixime or the cefixime placebo.  
 
Children will take the medication prescribed by their physician for five 
days. Prior to taking the sixth day of medication, children will be 
enrolled in the SCOUT study and randomized to either the standard 
course arm or short course arm. Children randomized to the standard 
course arm will receive five additional days of the initially prescribed 
antibiotic. Children randomized to the short-course therapy arm will 
receive five additional days of a liquid placebo in an equivalent weight-
based volume (same dosage mg/kg) to that of the antibiotic they would 
have received had they been in the treatment group for five additional 
days. The placebo will appear identical in color, taste, thickness, and 
consistency to the originally prescribed antibiotic. The study product 
kits will be similarly labeled with a numerical code that masks site 
investigators, site staff, parent(s)/guardian(s) and children to the 
formulation. 
 
Objectives: 
 
 
Primary Objective: 
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 TOC (visit Day 11-14) as subjects who continue to take 
antibiotics for an additional 5 days  (standard course therapy).  
Secondary Objectives:    
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). 
 
To determine if short-course therapy compared to standard course 
therapy results in similar numbers of children with asymptomatic 
bacteriuria.   
 
To determine if short-course therapy compared to standard course 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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therapy results in similar numbers of children with gastrointestinal 
colonization of antimicrobial resistant Escherichia coli (E. coli) and 
Klebsiella pneumonia (K. pneumoniae).  
 
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. 
 
To determine if the number of subjects with positive urine culture prior 
to or at TOC is similar after short-course therapy compared to standard 
course therapy.  
 
 
Description of Study 
Design: 
 
Investigators at or affiliated with one of the two clinical centers will refer 
children treated for a UTI. Children will be recruited from three different 
sources: primary or urgent care sites, general pediatrics inpatient units 
and the emergency departments. Children who meet the eligibility 
criteria and whose parent(s)/guardian(s) agree to participate in the 
study will be scheduled for an enrollment visit.  At the time of 
enrollment, children will be randomized to the standard-course arm or 
the short-course arm at a 1:1 ratio.  Subjects may be enrolled at any 
time following initiation of antibiotic therapy, providing they meet all 
inclusion/exclusion criteria.  However, all subjects will continue on the 
originally prescribed antibiotic treatment through the end of Day 5.  
Subjects enrolled Day 6 cannot have started the Day 6 of their 
originally prescribed antibiotic treatment.  Any volunteer that is enrolled 
and subsequently develops a fever or has worsening symptoms prior 
to starting SCOUT therapy on Day 6 will be withdrawn from the study 
and considered an entry failure.  For subjects enrolled prior to Day 5, 
confirmation from the parents will be obtained on Day 5 or Day 6 (prior 
to taking the first dose of SCOUT therapy on Day 6) that the subjects 
remain afebrile and have not had worsening of symptoms.  Any 
volunteer that develops a fever or worsening symptoms prior to 
initiating study treatment will be considered an entry failure.   
 
After enrollment, subjects will be scheduled for two follow-up visits and 
will receive a follow-up phone call at the end of the study: 
 
 Day 11 - 14 Test of Cure (TOC) Visit (One – four days after 
completing the study product).  Subjects will be evaluated for clinical 
symptoms of UTI and a urine sample will be collected for analysis from 
all subjects.  In addition, a stool sample will be obtained for 
assessment of antimicrobial resistant Escherichia coli (E .coli) and 
Klebsiella pneumoniae (K. pneumonia). 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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Day 24 - 30 Outcome Assessment Visit (14 - 20 days after completing 
the study product).  Subjects will be evaluated for clinical symptoms of 
UTI.  A urine sample will be collected only for those asymptomatic 
subjects for whom a urine sample could not be obtained at the TOC 
Visit and subjects that present with UTI symptoms at this visit.  In 
addition, a stool sample will be obtained for assessment of 
antimicrobial resistant Escherichia coli (E .coli) and Klebsiella 
pneumoniae (K. pneumonia). 
 
Day 38 - 44 Follow-Up Phone Call (28-34 days after completing the 
study product).  Subjects will be contacted by phone and asked about 
the presence of UTI symptoms.    
 
Follow-up for subjects that develop UTI throughout study 
Throughout the study, if a subject develops UTI symptoms, he/she will 
be evaluated by a SCOUT physician or if preferred, the child’s primary 
care provider.  This Interim Visit will be performed only to determine 
whether the child has a UTI, so no stool specimen will be collected. If 
the child has pyuria and the urine culture is positive, the symptomatic 
child will stop the study product (if during the Day 6-10 period), and will 
be treated outside this protocol by a physician not associated with the 
SCOUT Study per current standard of care or if they prefer the 
parent(s)/legal guardian(s) can choose to have their child treated by 
their PCP/pediatrician.  A SCOUT PI will follow up with the physician 
on the child’s status.  
Subjects that are diagnosed with a UTI while on study treatment and 
prior to the TOC Visit (between Day 6 and Day 11-14 TOC Visit) will be 
considered treatment failures and do not have to return for the TOC 
Visit but they will be asked to return for the Day 24-30 Outcome 
Assessment Visit and receive the Day 38-44 phone call.  Similarly, 
subjects that are diagnosed with a UTI at any time after the TOC Visit 
through the Day 38-44 call will continue to return for the Outcome 
Assessment Visit and receive the Day 38-44 follow-up phone call.   A 
stool specimen will still be collected at the Outcome Assessment Visit 
for these subjects diagnosed with UTIs (either before or after TOC). 
Sub-studies 
 
Seattle Children’s Hospital R21 
An R21-funded sub-study titled, “Differences in infecting and colonizing 
Enterobacteriaceae from short-course vs. standard therapy of pediatric 
UTI” is being performed with collaborators at Seattle Children’s 
Hospital. This sub-study hypothesizes that both the antibiotic agent 
and the length of therapy will affect the patients’ indigenous flora and 
thus affect both the likelihood of recovering E. coli and/or K. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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pneumoniae from stool and the resistance phenotypes of the 
recovered isolates. The sub-study will utilize PCR- and sequence-
based methods to characterize phylogenetic and resistance properties 
of the recovered isolates.  
 
Carbapenem resistant enterobacteriaceae 
For each enrolled research subject, the stool or perirectal swab 
collected at the Test of Cure visit will also be utilized to perform 
additional screening for the presence of carbapenem resistant 
enterobacteriaceae. The results of this additional screening will be 
used to determine the prevalence of colonization with carbapenem-
resistant Enterobacteriaceae (overall and for specific pathogens) in 
ambulatory children after completion of treatment for UTI. 
 
Microbiome pilot study 
For each subject at CHOP who agrees to participate in the Microbiome 
pilot study, an additional perirectal swab and anal swab will be 
collected. The additional swabs will be collected at each visit and will 
be used to determine the composition of the subjects’ microbiome. For 
subjects in diapers, an additional stool swab will also be collected. The 
accuracy of microbiome analysis resulting from perirectal swabs will be 
tested via comparison with analysis performed on stool specimens. 
The anal swab will be used to assess the presence of skin flora 
contamination in the peri-rectal swabs. 
 
Spectrum of Stool Bacteria 
For each enrolled research subject, the stool or perirectal swab 
collected at each visit will be used to identify any organisms present in 
the stool, including those identified in addition to the organisms of 
interest for the SCOUT study, E. coli and K. pneumoniae. These 
organisms that grow from SCOUT stool cultures are already identified 
as a result of the processing taking place for the SCOUT study. In this 
sub-study, the names of these other bacteria will be collected in a 
database to allow for a general description of the organisms that are 
present in children that are receiving antibiotic therapy for a urinary 
tract infection. 
Outcome Measures 
 
The primary outcome measure is: 
 
Comparison of efficacy, based on symptomatic UTI as assessed up to 
or at the TOC visit (Day 11-14), between short-course and standard-
course therapies. 
 
The secondary outcome measures are: 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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Comparison of number of subjects that have a recurrent infection 
(includes a relapse UTI or a reinfection) at any time after the TOC visit 
(Day 11-14), following short-course versus standard-course (of 
antibiotics.   
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 as assessed 
through Day 24-30, following short-course versus standard course of 
antibiotics. 
Comparison of the number of subjects with asymptomatic bacteriuria in 
subjects treated with short-course therapy as compared to the number 
of subjects treated with standard course therapy at the TOC visit 
Comparison of the number of subjects with clinical symptoms that may 
be related to a UTI in subjects treated with short-course therapy as 
compared to the number of subjects treated with standard course 
therapy prior to or at the TOC visit. 
Comparison of the number of subjects with positive urine culture prior 
to or at TOC between subjects treated with short-course therapy and 
those treated with standard course therapy. 
 
The sub-study outcome measures are: 
 
Seattle Children’s Hospital R21 
To determine if E. coli and K. pneumonia recovered from 2 or 3 stool 
cultures are more likely to be members of disease-associated 
subgroups within their respective species (E. coli phylogroups B2 and 
D, K. pneumoniae clusterKpI). 
 
To determine if treatment-susceptible strains recovered from cultures 
during treatment (culture #1 for 5-day arm; cultures #1 or #2, 10-day 
arm) are more likely to be members of disease-associated subgroups. 
 
To determine if treatment-resistant strains of either species are more 
likely than treatment susceptible strains to be recovered from cultures 
during treatment. 
 
Carbapenem resistant Enterobacteriaceae study 
To determine the overall prevalence of colonization with carbapenem  
resistant Enterobactericiae in children after completion of the course of 
antibiotic therapy for UTI 
 
Microbiome pilot study 
To determine the overall biodiversity of the gut microbial community, 
as measured by culture-independent marker gene sequencing at each 
follow-up visit following short-course and standard-course antibiotic 
exposure. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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To determine the overall fraction of gut microbiome community 
represented by gammaproteobacteria measured by culture-
independent marker gene sequencing at each follow-up visit following 
short-course and standard-course antibiotic exposure. 
 
To determine the average ecological similarity between microbial 
communities within and between treatment groups at each follow-up 
following short-course and standard-course antibiotic exposure. 
 
Spectrum of Stool Bacteria 
To describe the bacteria present on the aerobic stool cultures obtained 
at each of the three study time points.  
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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1 
KEY ROLES 
DMID Protocol Champion:   
Maureen Mehigan, RN  
Bacteriology and Mycology Branch 
Division of Microbiology and Infectious Diseases 
HHS/NIH/NIAID 
5601 Fishers Lane MSC 9826 
Room 7E19 
Rockville, MD.20892 
Tel: 240-627-3317 
Fax: 240-507-9599 
Email: mmehigan@niaid.nih.gov 
 
Principal Investigators:  
Theoklis Zaoutis, MD, MSCE 
Children’s Hospital of Philadelphia 
2716 South Street 10-473 
Philadelphia, PA  19146 
Phone: 267-426-5570 
Fax: 267-426-0380 
Email: Zaoutis@email.chop.edu  
 
Alejandro Hoberman, MD 
Children’s Oakland Medical Building 
3420 Fifth Avenue 
Pittsburgh, PA 15213 
Phone: 412-999-3277 
Fax: 412-692-5807 
Email: Hoberman@chp.edu  
DMID Medical Monitor: 
 
Venus Shahamatdar, MD 
 
 
 
Statistician: 
NIH/NIAID/DMID/OCRA  
5601 Fishers Lane MSC 9826 
Room 7E54 
Bethesda, MD.20892-9826 
Tel: 240-627-3369 
Email:  venus.shahamatdar@niaid.nih.gov  
 
Okan Elci, PhD 
3535 Market St. #1042 
Philadelphia, PA 19104 
Phone: 215-590-4201 
Fax: 215-590-9183 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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2 
 
Email: OkanElci@westat.com  
  
Institutions: 
 
Children’s Hospital of Philadelphia 
34th Street Civic Center Boulevard 
Philadelphia, PA 19104 
 
Children’s Hospital of Pittsburgh of the University of Pittsburgh 
Medical Center  
Children's Hospital Drive 
45th St. & Penn Ave. 
Pittsburgh, PA 15201 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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3 
 
2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 Background Information 
UTI 
Urinary tract infections (UTIs) are among the most common bacterial infections 
encountered by primary care physicians. UTI is one of the most common serious bacterial 
infections during childhood [1]. Estimates of the cumulative incidence of UTI in children 
under age six years (three – seven percent in girls and one – two percent in boys) suggest 
that between 70,000 to 180,000 of the annual US birth cohort will have a UTI by age six 
[2]. 
Escherichia coli (E. coli) isolates account for 80-90% of all outpatient UTIs in both children 
and adults [10-12]. The remaining causes are other Gram-negative enterobacteria, 
especially Klebsiella, Proteus mirabilis, and Pseudomonas aeruginosa. Klebsiella 
pneumoniae (K. pneumonia) is a very important pathogen, both in its frequency of being 
associated with infection as well as in its tendency towards acquiring antimicrobial 
resistance.  
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. In 
many series, K. pneumoniae is an important cause of community acquired urinary tract 
infection in children and is an even more important cause of nosocomial infection in this 
population. 
 
 
Emergence of Antimicrobial Resistance 
The rapid emergence of antimicrobial resistance among bacteria is a major threat to the 
health of individuals as well as society as a whole.  Infections with resistant bacteria 
increase morbidity and mortality, and greatly increase the financial burden of medical care 
[3-6]. While the number of resistant bacteria and the diversity of molecular mechanisms of 
resistance have increased sharply in recent years [7-8], the introduction of newer, effective 
antimicrobials has slowed significantly [9]. 
Antimicrobial resistance among uropathogens is increasing, especially among E. coli 
isolates [10-12]. K. pneumoniae account for a significant proportion of UTIs caused by 
non-E. coli organisms and resistant K. pneumoniae are increasingly prevalent and 
increasingly resistant to many antimicrobial agents including the broadest spectrum 
antimicrobial agents, the carbapenems [13-15]. The most significant change has been the 
rapid rise in prevalence of invasive infections caused by uropathogens resistant to 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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trimethoprim-sulfamethoxazole (TMP-SMX), ampicillin, and cephalosporins in both adults 
and children [10, 12, 16]. Of particular concern is the alarmingly high rate of resistance to 
third-generation cephalosporins in children admitted to the hospital for UTIs at some 
institutions [17]. Because these antimicrobial agents are commonly used as empiric 
therapy for UTI, emerging antimicrobial resistance has posed a significant challenge for 
clinicians. Timely and appropriate antibiotic therapy for UTIs in children, especially within 
24 hours of onset of symptoms, reduces the risk of renal involvement. In addition, 
resistance to one class of antimicrobial agents used to treat UTIs has been associated 
with concurrent resistance to other antimicrobials [18]. For example, resistance to TMP-
SMX has been associated with resistance to ampicillin, cephalothin, and third-generation 
cephalosporins [19-21]. Thus, the potential emergence of multi-drug resistant 
uropathogens is of great concern. 
 
Table 1: Percent Isolates Susceptible to Each Antibiotic  
ORGANISMS   
Amikacin 
Ampicillin 
Amox/Clav 
Amp/Sulb 
Aztreonam 
Cefazolin 
Ceftazidime 
Cefepime 
Cefoxitin 
Ceftriaxone 
Cefuroxime 
Ciprofloxacin 
Gentamicin 
Imipenem 
Meropenem 
Nitrofurant 
Pip/Tazo 
Tetracycline 
Ticar/Clav 
Tobramycin 
Trimeth/Sulf 
Escherichia coli  
CHOP 
 
54 
78 
 
 
93 
99 
 
96 
99 
93 
92 
94 
 
 
96 
 
80 
89 
97 
78 
PITT 
99 
52 
82 
96 
87 
96 
97 
 
96 
93 
92 
95 
99 
 
 
79 
96 
 
 
94 
79 
Klebsiella pneumonia 
CHOP 
 
0 
93 
 
 
93 
94 
 
94 
94 
88 
97 
94 
 
 
33 
 
86 
94 
94 
85 
PITT 
99 
0 
85 
 
82 
73 
81 
83 
 
83 
69 
88 
97 
 
 
67 
83 
 
 
87 
67 
 
Evidence that Shorter Treatment Courses May Be Safe and Effective 
Long-course antibiotic therapy for UTIs is intended to target the uropathogens, such as E. 
coli, but also alters the micro-ecology of the intestinal flora and its antibiotic resistance 
pattern, leading to prolonged colonization with antibiotic resistant E. coli that may persist 
for months [22]. This not only affects the individual child, but other community members as 
well. Studies have demonstrated that colonization with antimicrobial-resistant E. coli 
predisposes individuals who develop UTI to be infected with a resistant strain [23, 24]. 
Colonization with antimicrobial-resistant E. coli can be spread from the one child to the 
other within day care centers and from day care center contacts to household members 
[25-28]. Thus, children in day care represent a significant reservoir of potential resistant 
pathogens and day care attendance facilitates broad transmission throughout a 
community, expanding the numbers of individuals at risk of infection due to a resistant 
organism.  


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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2.2 
Rationale 
The American Academy of Pediatrics (AAP) Practice Parameter for the treatment of UTI 
in infants and young children recommends a seven to 14-day antibiotic course, however 
most physicians routinely prescribe at least 10 days of antibiotic treatment. CHOP’s 
Infectious Diseases research group recently published the results of a large cohort study 
of patients with UTI in 27 primary care pediatric practices and found that greater than 
95% of UTIs were treated with a 10 to 14-day course of antibiotics [44]. Therefore, the 
large number of children with UTI and the duration of therapy in current standard 
practice make UTI an important target for reducing antibiotic exposure. Randomized 
clinical trials over the last 25 years have not provided definitive evidence supporting 
seven -14 day antibiotic courses for children with UTI. In fact, most studies showed no 
statistically significant difference in efficacy between short- and long-course antibiotic 
therapies. Although many of these studies were limited by small sample size, meta-
analyses that pool the study results have shown similar results. Keren (a SCOUT co-
investigator) and colleagues found that single dose or one-day of therapy was 
associated with a pooled relative risk of treatment failure of 2.73 (95%CI: 1.38-5.40) 
when compared to patients treated for seven -14 days [43]. However, for the subgroup 
of studies comparing three-day therapy to long-course therapy (seven-14 days), there 
was no increased risk of treatment failure (pooled RR 1.36 (95% CI: 0.69-2.72)). Tran, et 
al. in a meta-analysis of 1,279 children treated with either four days or less of therapy or 
with five days or more of therapy; they also noted no difference in the risk of treatment 
failure [44]. A single dose of amoxicillin was inadequate therapy for uncomplicated 
cystitis in children, however, three days of trimethoprim-sulfamethoxazole (TMP-SMX) 
was as effective as longer courses of therapy of TMP-SMX [44]. The Cochrane group 
conducted a systematic review comparing short course (two - four days) with standard 
duration (seven -14 days) of antimicrobial therapy for lower tract (e.g. cystitis) UTI in 
children [45]. Short-course antimicrobial therapy was found to be as effective as seven-
14 days in eradicating lower tract UTI in children. In summary, meta-analyses suggest 
that treatment of UTI in children should not be less than three days, but that treatment 
with three or more days of therapy approaches treatment success of long-course 
therapy (seven -14 days). 
Due to the frequency of UTIs in children, the duration of currently used antibiotic therapy, 
and the limitations of previous studies investigating the effectiveness of shorter-courses 
of therapy, there is a need for an adequately powered and well-designed trial to 
determine the efficacy and safety (e.g. incidence/severity of SAEs) of shorter course 
antibiotic therapy. Shortening antibiotic duration for UTIs and other infections reduces 
antibiotic exposure and should decrease the development of antimicrobial resistance. 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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Rationale for Studying Urinary Tract Infections in Children 
SCOUT will evaluate shorter courses of antibiotics for UTIs in children because: 
(1) UTIs are common;  
(2) UTIs are currently treated with a long course of antibiotics (10-14 days);  
(3) There is evidence that shorter treatment courses may be safe and effective; and  
(4) Antibiotic resistance among uropathogens (e.g. E. coli and K. pneumoniae) has a 
significant clinical and public health impact.  
 
Rationale for Shorter Antimicrobial Treatment Duration 
A commonly proposed strategy to reduce antimicrobial resistance is to limit antimicrobial 
use to the minimum duration necessary for safe and effective treatment [14].  
Decreasing the duration of antimicrobial therapy reduces antimicrobial selection 
pressure on colonizing and environmental flora, which should decrease their acquisition 
of antimicrobial resistance. Antibiotic pressure, which promotes the exchange of 
resistance genes by various transfer mechanisms, has been proven to be the single 
most important factor predisposing patients to infection with resistant organisms [29]. On 
a population level there is a clear relationship between total antibiotic consumption and 
resistance rates among bacterial pathogens [30-32].  Multiple clinical studies have 
documented an association between prolonged courses of therapy and the development 
of resistance in individual patients during therapy [33-35]. In fact, antimicrobial exposure 
is one of the most common risk factors for colonization and infection with antibiotic-
resistant organisms [35].  
The basis for currently prescribed lengths of antibiotic therapy for most infectious 
diseases is largely historical, and not evidence-based. Because of the lack of data 
regarding the minimum effective duration of therapy, physicians often extend 
antimicrobial courses well beyond the time of clinical improvement. However, shorter 
courses of therapy have been shown to be effective in treating several infectious 
diseases, including traveler’s diarrhea, community-acquired pneumonia, ventilator-
associated pneumonia, cystitis in adults, acute otitis media, pharyngitis, and cellulitis [34, 
36-42]. 
 
Antibiotic Resistance among Uropathogens (e.g. E. coli and K. pneumoniae) has a 
Significant Clinical and Public Health Impact  
Antimicrobial resistance among uropathogens is increasing, especially among E. coli 
isolates, which account for 80-90% of all outpatient UTIs in both children and adults [10-
12]. K. pneumoniae account for a significant proportion of UTIs caused by non-E. coli 
organisms and resistant K. pneumoniae are increasingly prevalent and increasingly 
resistant to many antimicrobial agents including the broadest spectrum antimicrobial 
agents, the carbapenems [40-42]. The most significant change has been the rapid rise in 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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7 
 
prevalence of invasive infections caused by uropathogens resistant to TMP-SMX, 
ampicillin, and cephalosporins in both adults and children [10,12,16]. Of particular 
concern is the alarmingly high rate of resistance to third-generation cephalosporins in 
children admitted to the hospital for UTIs at some institutions [17]. Because these 
antimicrobial agents are commonly used as empiric therapy for UTI, emerging 
antimicrobial resistance poses a significant challenge for clinicians. Timely and 
appropriate antibiotic therapy for UTI in children, especially within 24 hours of onset of 
symptoms, reduces the risk of renal involvement [18]. In addition, resistance to one class 
of antimicrobial agents used to treat UTI has been associated with concurrent resistance 
to other antimicrobials. For example, resistance to TMP-SMX has been associated with 
resistance to ampicillin, cephalothin, and third-generation cephalosporins [19-21]. Thus, 
the emergence of multi-drug resistant uropathogens is of great concern. 
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
 
Short-course Antimicrobial Therapy Arm:  
Five Days of Antibiotics + Five Days of the Placebo 
Five days of antibiotic therapy may be less effective than 10 days, and so children in the 
short-course five-day arm may have a higher risk of treatment failure. The risk is 
mitigated by the fact that only those children that have shown clinical improvement 
(afebrile and asymptomatic) after initiation of antibiotic therapy will be enrolled in the 
study.  This is one reason why subjects are enrolled following initiation of antibiotic 
therapy, rather than prior to initiation.  
 
Standard-of-Care Antimicrobial Therapy Arm: 10 Days of Antibiotics 
Long-course antibiotic therapy for UTI is intended to target the uropathogens, such as E. 
coli and K. pneumoniae, but also alters the micro-ecology of the intestinal flora and its 
antibiotic resistance pattern, leading to prolonged colonization with antibiotic resistant E. 
coli and K. pneumoniae that may persist for months [22]. This not only affects the 
individual child, but other community members as well. Studies have demonstrated that 
colonization with antimicrobial-resistant E. coli and K. pneumoniae predisposes 
individuals who develop UTI to be infected with a resistant strain [23-24]. 
Children on the continued antibiotic treatment arm may have a higher likelihood of 
developing resistant bacteria than children on the placebo arm; however, their risk will 
be no greater than what occurs in standard clinical practice. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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Drug Safety 
The antibiotics used in this study (trimethoprim-sulfamethoxazole (TMP-SMX) or 
cefixime or cephalexin) are not investigational drugs and are already used in current 
clinical practice to treat UTIs. Subjects on the continued antibiotic arm will receive the 
same antibiotic initially prescribed to them that they would have completed if not part of 
the SCOUT clinical study.  Note:  subjects initially prescribed cefdinir will receive 
cefixime or cefixime placebo. 
Trimethoprim-sulfamethoxazole (TMP-SMX), cefixime, cefdinir, and cephalexin have 
been used to treat UTIs in children for decades. These four antibiotics have established 
safety records for pediatric use and have well described side effect profiles. Antibiotics 
disturb the normal bowel bacterial flora.  During study visits and the follow-up phone call, 
study participants will be asked to report any potential side effects of the study product, 
any residual UTI symptoms, and if the child had any hospital or doctor visits for UTI 
symptoms since their last study contact, and on any possible adverse reactions. All 
potential serious adverse events (SAEs) or reported side effects will be recorded as 
study data. 
Although the study is using four FDA-approved antibiotics, this study will be conducted 
under an IND because it will be used to inform the medical community regarding 
alternative treatment regimens for the antibiotic treatment duration.  
 
Trimethoprim-Sulfamethoxazole (TMP-SMX) 
TMP-SMX may cause allergic reactions that range from a mild (skin rash) to severe 
(Stevens - Johnson syndrome), although severe reactions are extremely rare. Other 
potential side effects of TMP-SMX include sun sensitivity, recurrent vaginitis, 
granulocytopenia, and dizziness. Families will be queried about a subject’s history of 
allergies to TMP-SMX. Families will be provided with literature on adverse reactions to 
TMP-SMX and instructions to call study staff if any evidence of such a reaction occurs.  
 
Cefixime 
Cefixime should be avoided by children with a known allergy to cephalosporin type 
antibiotics. Cefixime is generally well tolerated and side effects are usually transient. 
Cefixime may cause gastrointestinal issues such as diarrhea, gas, and stomach pain, as 
well as more severe events such as bloody stools, severe nausea or vomiting or allergic 
reactions. Families will be queried about a subject’s history of allergies to cefixime. 
Families will be provided with literature on adverse reactions to cefixime and instructions 
to call study staff if any evidence of such a reaction occurs. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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Cefdinir 
On occasion cefixime may not be available to the prescribing primary care physician.  
Under such circumstances it is likely that cefdinir will be prescribed as an alternative 
agent to cefixime instead. The two antibiotics have therapeutic equivalence. 
If a subject prescribed cefdinir is enrolled and randomized they will be given either five 
additional days of cefixime (standard-of-care) or the cefixime placebo (short-course) for 
the day six – ten SCOUT Study period. Families will be queried about a subject’s history 
of allergies to cefixime. Families will be provided with literature on adverse reactions to 
cefixime and instructions to call study staff if any evidence of such a reaction occurs. 
 
Cephalexin 
 
Cephalexin should be avoided by children with a known allergy to penicillin or 
cephalosporin type antibiotics. Allergic reactions in the form of rash, urticaria, 
angioedema, and, rarely, erythema multiforme, Stevens-Johnson syndrome, or toxic 
epidermal necrolysis have been observed. These reactions usually subsided upon 
discontinuation of the drug. Cephalexin may cause gastrointestinal issues including 
pseudomembranous colitis, diarrhea, dyspepsia, gastritis, and abdominal pain. Families 
will be provided with literature on adverse reactions to cefixime and instructions to call 
study staff if any evidence of such a reaction occurs. 
Risks Associated with Catheterization 
If a clean-catch sample cannot be obtained in a symptomatic subject a catheter obtained 
sample should be obtained.    
 
Catheterization will be performed as a sterile medical procedure and will only be done by 
trained, qualified clinicians, using equipment designed for infants and young children. If 
correct technique is not used, there may be risks of urinary catheterization including: 
 
• 
injury to the urethra and prostate (male) caused by traumatic insertion of the 
catheter;  
• 
narrowing of the urethra due to scar tissue caused by the insertion of a catheter; 
and 
• 
injury to the bladder caused by incorrect insertion of the catheter; 
• 
catheter associated urinary tract infection; 
• 
pain and discomfort; 
• 
paraphimosis in an uncircumcised male. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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The SCOUT Study Nurses/Nurse Practitioners/Physicians will take all possible 
precautions to reduce the risk of infection. Such precautions include: 
• 
Cleansing the urethral area (area where catheter exits body) and using a sterile 
catheter; 
• 
The catheter will be lubricated with a water-soluble sterile lubricant prior to 
insertion; 
• 
Disconnecting drainage bag from catheter only with clean hands; and 
• 
Use of a thin (age and size appropriate) catheter to reduce risk of harming the 
urethra during insertion.  
These potential risks will be shared with the child’s family and outlined in the informed 
consent form. 
Risks Associated with Rectal Swab 
Performing a rectal swab for the collection of stool sample has almost no risk.  Some 
parents and children find it aesthetically unpleasant.  For some older children, it may be 
psychologically distressing. 
 
Potential Loss of Confidentiality 
SCOUT will institute strict procedures to maintain confidentiality.  No personal 
information, such as names, contact information, social security numbers, etc. will be 
stored in the study database managed by the CHOP-Westat BDMC. Information such as 
dates of birth and dates of events will be stored in the database by study ID number. 
Physical files linking study ID numbers to personal information will reside in locked files 
in the office of the Principal Investigator or the Study Coordinator at the clinical site.  Any 
publications or presentations resulting from this work will not identify participants by 
name, but will only present aggregate data.  Our prior research employing similar 
precautions has demonstrated that these techniques are very successful in assuring the 
protection of subjects. Genetic testing is not planned; however, there may be future 
bacterial genomic testing to determine the mechanism of resistance and epidemiological 
relationships. 
 
Protection against Risks to Study Personnel 
The only potential hazard to study personnel is exposure to feces and urine when the 
Study Nurse/Nurse Practitioner/Physician collects the stool and urine sample. All the 
study personnel that may be exposed will be trained in safety precautions.  
 
Study staff will be trained according to the International Air Transport Association (IATA) 
requirements before shipping stool samples to the PITT IDRL. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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2.3.2 Potential Benefits 
There is the possibility of direct benefit to the subject enrolled in this study.   Study 
subjects in the short course arm may experience decrease antibiotic side effects and a 
reduction in opportunistic or secondary infections such as vaginitis. 
Also, information obtained from this study may show if shortening antibiotic duration for 
UTI decreases the development of antimicrobial resistance as well as help preserve the 
effectiveness of existing antimicrobials.  The results of this study will assist health-care 
providers in making decisions regarding the use of antimicrobial therapy for treating 
children with UTIs, and may benefit the health of the general community by slowing the 
evolution of antimicrobial resistance.  By reducing the occurrence of resistant organisms, 
society benefits through easier treatment of this common infection. Careful follow-up will 
allow for early termination of study participation in the case of children categorized as 
treatment failures. 
The SCOUT Study will provide data to guide the future effective management of 
pediatric UTIs using strategies aimed to control the emergence of antimicrobial 
resistance among bacteria. 
 
 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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3 
DEFINITIONS 
Fever/Febrile: A documented temperature of at least 100.4° F or 38° C, measured anywhere on 
the body (oral, axillary, tympanic, or rectal). 
 
Afebrile: NO documented temperature greater than or equal to 100.4 °F or 38°C, measured 
anywhere on the body (oral, axillary, tympanic, or rectal) in the 24 hours prior to the enrollment 
visit. 
Urinary Tract Infection: 
I.  The presence (in the medical record or by parent report) of at least one of the 
symptoms consistent with the diagnosis of UTI including: 
• Symptoms for all children (ages two months to 10 years): 
o fever (a documented temperature of at least 100.4 °F OR 38°C measured 
anywhere on the body)  
o dysuria  
• Additional symptoms for children > 2 years of age:  
o suprapubic, abdominal, or flank pain or tenderness OR 
o 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:  
o poor feeding OR 
o vomiting 
AND 
II. Pyuria on urinalysis 
•  >10 WBC/mm3 (uncentrifuged specimen) OR 
•  >5 WBC/hpf (centrifuged specimen), OR 
• Leukocyte esterase > trace on dipstick. 
AND 
III. Culture proven infection with a single uropathogen: 
•   >5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen) OR 
•   >105 CFU/mL (clean void specimen). 
 
Prescription medication: Medication prescribed by an authorized/licensed clinician.   
 
Study product: The term ‘study product’ refers to both the study antibiotic (TMP-SMX, cefixime, 
and cephalexin) and the corresponding placebo. 
 
Clinical Improvement at Randomization: 
1) Afebrile: No documented temperature equal or greater  than 100.4 °F or 38°C, measured 
anywhere on the body (oral, axillary, tympanic, or rectal) in the 24 hours prior to the 
Enrollment Visit 
AND 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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13 
 
2) Asymptomatic: Report NONE of the following symptoms related to UTI: 
• Symptoms for all children (ages two months to 10 years): 
o fever (a documented temperature of at least 100.4 °F OR 38°C measured anywhere 
on the body)  
o dysuria  
• Additional symptoms for children > 2 years of age:  
o suprapubic, abdominal, or flank pain or tenderness OR 
o 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:  
o poor feeding OR 
o vomiting 
 
Treatment Failure:  
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: (See Appendix B) 
• Symptoms for all children (ages two months to 10 years): 
o fever (a documented temperature of at least 100.4 °F OR 38°C measured 
anywhere on the body)  
o dysuria  
• Additional symptoms for children > 2 years of age:  
o suprapubic, abdominal, or flank pain or tenderness OR 
o 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:  
o poor feeding OR 
o vomiting 
AND 
I. Pyuria on urinalysis 
•  >10 WBC/mm3 (uncentrifuged specimen) OR 
•  >5 WBC/hpf (centrifuged specimen), OR 
Leukocyte esterase > trace on dipstick. 
AND 
II. Culture proven infection with a single uropathogen:  
•  >5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen) OR 
•   >105 CFU/mL (clean void specimen). 
 
 
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. 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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Pyuria on urinalysis: 
• 
>10 WBC/mm3 (uncentrifuged specimen) OR 
• 
>5 WBC/hpf (centrifuged specimen), OR 
• 
Leukocyte esterase > trace on dipstick. 
 
Recurrent Infection: A UTI that occurs anytime after the Day 11 – 14 Test of Cure Visit. This 
can include a relapse infection or reinfection. (See Appendix B) 
 
Asymptomatic Bacteriuria:  
Asymptomatic Bacteriuria is defined in any SCOUT subject by: 
(1) Absence of symptoms attributable to UTI including fever AND/OR the following: 
• Symptoms for all children (ages two months to 10 years): 
o fever (a documented temperature of at least 100.4 °F OR 38°C measured 
anywhere on the body)  
o dysuria  
• Additional symptoms for children > 2 years of age:  
o suprapubic, abdominal, or flank pain or tenderness OR 
o 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:  
o poor feeding OR 
o vomiting 
      AND 
 
(2) A positive urine culture with a single uropathogen: 
•   > 5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen) OR 
•   >105 CFU/mL (clean void specimen). 
 
Diarrhea: Three loose, watery stools that occur in one day or two or more loose, watery stools 
in two consecutive days. 
 
Antibiotic Resistance: Resistance against amoxicillin-clavulanate, TMP-SMX or evidence of 
ESBL production.  
 
Multiple Drug Antibiotic Resistance: Resistance to two or more agents (this includes 
resistance against amoxicillin and amoxicillin-clavulanate). 
 
 K. pneumoniae Multiple Drug Antibiotic Resistance: Resistance to either two or more of the 
four agents (TMP-SMX, amoxicillin-clavulanate, cefixime or cephalexin) that the SCOUT Study 
will test (excluding amoxicillin resistance). Those initially prescribed cefdinir are switched to 
bioequivalent cefixime. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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4 
OBJECTIVES 
4.1 
Study Objectives 
 
The primary and secondary objectives of this study are as follows: 
 
Primary Objective: 
 
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 TOC (visit Day 11-14) as subjects who 
continue to take antibiotics for an additional 5 days  (standard course therapy). 
 
Secondary Objectives: 
 
To determine if short-course therapy compared to standard course therapy results in 
similar numbers of children experiencing a recurrent infection (relapse and reinfection). 
 
To determine if short-course therapy compared to standard course therapy results in 
similar numbers of children with asymptomatic bacteriuria.   
 
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 pneumoniae (K. pneumoniae).  
 
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. 
 
To determine if short-course therapy compared to standard course therapy results in 
similar numbers of subjects with positive urine cultures up to and including TOC. 
 
Sub-Study Objectives: 
 
Seattle Children’s Hospital R21 
To determine if E. coli and K. pneumonia recovered from 2 or 3 stool cultures are more 
likely to be members of disease-associated subgroups within their respective species (E. 
coli phylogroups B2 and D, K. pneumoniae clusterKpI). 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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To determine if treatment-susceptible strains recovered from cultures during treatment 
(culture #1 for 5-day arm; cultures #1 or #2, 10-day arm) are more likely to be members 
of disease-associated subgroups. 
 
To determine if treatment-resistant strains of either species are more likely than 
treatment susceptible strains to be recovered from cultures during treatment. 
 
Carbapenem resistant Enterobacteriaceae study 
To determine the overall prevalence of colonization with carbapenem resistant 
Enterobactericiae in children after completion of the course of antibiotic therapy for UTI 
 
Microbiome pilot study 
To determine the overall biodiversity of the gut microbial community, as measured by 
culture-independent marker gene sequencing at each follow-up visit following short-
course and standard-course antibiotic exposure. 
 
To determine the overall fraction of gut microbiome community represented by 
gammaproteobacteria measured by culture-independent marker gene sequencing at 
each follow-up visit following short-course and standard-course antibiotic exposure. 
 
To determine the average ecological similarity between microbial communities within 
and between treatment groups at each follow-up following short-course and standard-
course antibiotic exposure. 
 
 
Spectrum of Stool Bacteria 
To describe the breadth of bacteria present in the stool of children receiving therapy for 
a urinary tract infection. These data will allow for comparison of aerobic bacteria 
composition in these children and present an opportunity to contrast them to similar data 
available from other pediatric patient populations.   


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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1 
 
 
4.2 
Study Outcome Measures 
In order to capture all cases of UTI, and to enhance our ability to identify any symptom 
related to the urinary tract, we modeled when to have our follow up study visits and 
phone call after the FDA’s Guidance for Complicated and Uncomplicated Urinary Tract 
Infections [51,52].  We will have the: 
1) Test-of-Cure Post-Treatment (TOC) Visit on Day 11 -14 (FDA recommendation: 
five - nine days after completing the study product); in order to evaluate the 
primary endpoint of symptomatic UTI.  Secondary endpoints of asymptomatic 
bacteriuria, positive urine culture, and presentation of clinical symptoms that may 
be related to UTI will also be assessed. 
2) Outcome Assessment Visit on Day 24 – 30 (14 – 20 days after completing the 
study product) in order to evaluate the secondary  endpoints: recurrent infection 
(includes a relapse UTI or a reinfection) at any time after the TOC visit (Day 11-
14); colonization with antimicrobial resistant E. coli and K. pneumoniae in the 
gastrointestinal tract; and  
3) Follow-up call on Day 38 – 44 (FDA: 28-34 days after completing the study 
product). Safety follow-up during which subjects will be asked regarding 
presence or absence of UTI symptoms, if they sought medical care for possible 
recurrence of UTI, and if they experienced any inter-current illnesses. 
 
4.2.1 Primary and Secondary Outcome Measures 
The primary outcome measure is: 
• 
Comparison of efficacy based on symptomatic UTI as assessed at the TOC visit 
(Day 11-14), between short-course and standard-course of antibiotics. 
Since the primary objective of the study is to establish that short-course therapy is as 
effective as the standard therapy, the analysis of the primary endpoint will be based on a 
non-inferiority test. The primary analysis will be done on the intent to treat (ITT) 
population. 
The secondary outcome measures are: 
• 
Comparison of the number of subjects that have a recurrent infection (includes a 
relapse UTI or a reinfection) at any time after the TOC visit (Day 11-14), following 
short-course versus standard-course of antibiotics.   
• 
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 as assessed through Day 24-30, following short-course 
versus standard course of antibiotics. 
• 
Comparison of the number of subjects with asymptomatic bacteriuria at the TOC 
visit, following short-course versus standard-course of antibiotics. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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• 
Comparison of the number of subjects with clinical symptoms that may be related 
to a UTI prior to or at the TOC visit, following short-course versus standard-
course of antibiotics. 
• 
Comparison of the number of subjects with positive urine cultures prior to or at 
the TOC visit, following short-course versus standard-course of antibiotics. 
For a summary of individual subject study outcomes against the primary outcome 
measure see Table 2. 
 
Sub-study Outcome Measures: 
Seattle Children’s Hospital R21 
• 
Presence of E. coli, presence of K. pneumoniae  
• 
Sub-types of E. coli (0=phylogroups A or B1, 1=phylogroups B2 or D), sub-types 
of K. pneumoniae  
• 
Presence of treatment-susceptible E. coli, presence of treatment-susceptible K. 
pneumoniae  
• 
Presence of treatment-resistant E. coli, presence of treatment-resistant K. 
pneumoniae  
Carbapenem resistant Enterobacteriaceae study 
• 
Prevalence of colonization with carbapenem resistant Enterobactericiae in 
children after completion of the course of antibiotic therapy for UTI  
 
Microbiome pilot study 
• 
Comparison of the overall biodiversity of the gut microbial community, as 
measured by culture-independent marker gene sequencing at each follow-up 
visit following short-course and standard-course antibiotic exposure. 
• 
Comparison of overall fraction of gut microbiome community represented by 
gammaproteobacteria measured by culture-independent marker gene 
sequencing at each follow-up visit following short-course and standard-course 
antibiotic exposure. 
• 
Comparison of average ecological similarity between microbial communities 
within and between treatment groups at each follow-up following short-course 
and standard-course antibiotic exposure. 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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Spectrum of Stool Bacteria 
• 
Description of the bacteria present on the aerobic stool cultures obtained at each 
the three study time points.


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                                  
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 9/20/2018 
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Table 2:  SCOUT Study Possible Outcomes Day 6-44. 
 
Outcome 
scenario 
UTI 
Symptomology 
Urine 
collection 
method 
Urine 
culture 
result 
Pyuria 
present 
Composite 
Outcome/Follow-up 
Repeat urine culture 
result/outcome 
Symp 
Asymp1 
+ 
- 
Yes 
NO 
1 
X 
 
Clean 
Catch or 
Catheter 
X 
 
X 
 
Treatment Failure 
 
 
2 
X 
 
Clean 
Catch or 
Catheter 
X 
 
 
X 
No UTI 
 
 
3 
X 
 
Clean 
Catch or 
Catheter 
 
X 
X 
 
Follow-up required.   
Contact subject in 24-
48 hrs.  Perform repeat 
urine culture if still 
symptomatic. 
+ 
 
Treatment 
Failure1 
- 
 
No UTI 
4 
X 
 
Clean 
Catch or 
Catheter 
 
X 
 
X 
Follow-up required.  
Contact subject in 24-
48 hrs - Perform repeat 
urine culture if still 
symptomatic. 
+ 
 
No UTI (since 
no Pyuria) 
- 
 
No UTI 
5a 
 
X 
Clean 
Catch 
X 
 
X 
 
No UTI (Asymptomatic 
Bacteriuria) 
 
 
5b 
 
X 
Bag 
X 
 
X 
 
No UTI (Asymptomatic 
Bacteriuria) 
  
 
6a 
 
X 
Clean 
Catch 
X 
 
 
X 
No UTI (Asymptomatic 
Bacteriuria) 
 
 
6b 
 
X 
Bag 
X 
 
 
X 
No UTI (Asymptomatic 
Bacteriuria) 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                                  
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 9/20/2018 
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5 
 
7 
 
X 
Clean 
Catch or 
Bag 
 
X 
X 
 
No UTI 
 
 
8 
 
X 
Clean 
Catch or 
Bag 
 
X 
 
X 
No UTI 
 
 
 
1  If a urine sample cannot be obtained from asymptomatic subjects at the TOC visit, another attempt will be made to obtain a sample 
at the Day 24-30 Outcome Assessment Visit.  These subjects are evaluable for the primary endpoint measure (considered a 
success); however, they will not be evaluable for the asymptomatic bacteriuria or urine culture secondary endpoints.   
 
Note:  Urine collection in children that are toilet trained will be by clean catch. For infants and young children (prior to being toilet 
trained) the initial urine sample will be obtained by bag method (if asymptomatic), clean-catch if symptomatic (or catherization if a 
sample cannot be obtained by clean-catch).  Also see Section 9.2.3.1 for listing of urine collection by age group/symptomology. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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6 
 
5 STUDY DESIGN 
The SCOUT Study is a multi-center, centrally randomized, double-blind, placebo-controlled non-
inferiority clinical trial. Children will be stratified based on the presence of fever at initial 
presentation of UTI symptoms and by specific antibiotic therapy prescribed by the original 
treating clinical provider. Children who have demonstrated clinical improvement five days after 
starting the originally prescribed antibiotic (afebrile and asymptomatic) will be randomized to 
standard arm or the short-course arm.  Subjects enrolled prior to completion of Day 5 of their 
originally prescribed antibiotic treatment, will be instructed to complete Day 5 dosing prior to 
initiating SCOUT study product on Day 6.  Subjects enrolled Day 6 should not have started the 
Day 6 of their originally prescribed antibiotic treatment.  The SCOUT study product will consist 
of trimethoprim-sulfamethoxazole sulfamethoxazole (TMP-SMX), cefixime, cephalexin and the 
corresponding placebos.  If a child initially prescribed cefdinir is enrolled, they will be 
randomized to either five additional days of cefixime or the cefixime placebo.  
About 746 subjects will be enrolled in order to reach 672 evaluable subjects, but the total 
number that will be ‘enrolled / consented’ may exceed 746 if the study has not enrolled 672 
evaluable for the primary endpoint.  
 
 
Figure 1: Randomization 
 
5.1 Sub-studies  
Seattle Children’s Hospital R21 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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An R21-funded sub-study titled, “Differences in infecting and colonizing Enterobacteriaceae 
from short-course vs. standard therapy of pediatric UTI” is currently planned with collaborators 
at Seattle Children’s Hospital. This sub-study hypothesizes that both the antibiotic agent and the 
length of therapy will affect the patients’ indigenous flora and thus affect both the likelihood of 
recovering E. coli and/or K. pneumoniae from stool and the resistance phenotypes of the 
recovered isolates. The sub-study will utilize PCR- and sequence-based methods to 
characterize phylogenetic and resistance properties of the recovered isolates. The sub-study 
will also test the  hypothesis that (1) E. coli and K. pneumonia recovered from 2 or 3 stool 
cultures are more likely to be members of disease-associated subgroups within their respective 
species (E. coli phylogroups B2 and D, K. pneumoniae cluster KpI); (2) treatment-susceptible 
strains recovered from cultures during treatment (culture #1 for 5-day arm; cultures #1 or #2, 10-
day arm) are more likely to be members of disease-associated subgroups; (3A) treatment-
resistant strains of either species are more likely than treatment susceptible strains to be 
recovered from cultures during treatment; and (3B) treatment susceptible strains of either 
species are more likely to be recovered from cultures during treatment in the AMC arm than in 
the TMP/SMX or CFX/CFD arms.  
 
Carbapenem resistant enterobacteriaceae 
For each enrolled research subject, the stool or perirectal swab collected at the Test of Cure 
visit will also be utilized to perform additional screening for the presence of carbapenem 
resistant enterobacteriaceae. The results of this additional screening will be used to determine 
the prevalence of colonization with carbapenem-resistant Enterobacteriaceae (overall and for 
specific pathogens) in ambulatory children after completion of treatment for UTI. 
 
Microbiome pilot study 
For each subject at CHOP who agrees to participate in the Microbiome pilot study, an additional 
perirectal swab and an anal swab will be collected. Subjects in diapers will also have a third 
additional stool swab collected if a soiled diaper can be obtained. The additional swabs will be 
collected at each visit and will be used to determine the composition of the subjects’ 
microbiome. Microbiome composition will be quantified using high-throughput DNA amplicon 
sequencing of 16S ribosomal RNA genes. The accuracy of microbiome analysis resulting from 
perirectal swabs will be tested via comparison with analysis performed on stool specimens. All 
samples will be shipped immediately or frozen overnight prior to shipment to collaborators at the 
University of Minnesota. Additionally, subjects agreeing to participate will be asked to complete 
a questionnaire providing data about feeding (breast milk, formula, timing of introduction of solid 
foods); most recent antibiotic prescriptions (name, dose, and duration); and number of antibiotic 
courses in life.    
 
Spectrum of Stool Bacteria 
For each enrolled research subject, the stool or perirectal swab collected at each visit will be 
used to identify any organisms present in the stool in addition to the organisms of interest for the 
SCOUT study, E. coli and K. pneumoniae. These organisms that grow from SCOUT stool 
cultures are already identified as a result of the processing taking place for the SCOUT study. In 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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8 
 
this sub-study, the names of these other bacteria will be collected in a database to allow for a 
general description of the organisms that are present in children that are receiving antibiotic 
therapy for a urinary tract infection. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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9 
 
6 STUDY ENROLLMENT AND WITHDRAWAL 
The two participating clinical trial centers, CHOP and PITT will enroll subjects over an 
approximately four and a half year enrollment period until 672 subjects have been enrolled that 
are evaluable for the primary outcome measure.  
 
6.1  
Subject Inclusion Criteria:  Must Meet All 
1) Age at randomization: at least two months (at least 36 weeks gestational age for 
subjects < two years of age) to 10 years of age (120 months) 
2) Confirmed UTI diagnosis (see definition Section 3) 
3) Documented Clinical Improvement at Randomization 
a. Afebrile : No documented temperature equal or greater  than 100.4 °F or 38°C 
(measured anywhere on the body) 24 hours prior to the enrollment visit 
AND 
b. Asymptomatic: report NONE of the following symptoms: 
• Symptoms for all children (ages two months to 10 years): 
o fever (a documented temperature of at least 100.4 °F OR 38°C measured 
anywhere on the body)  
o dysuria  
      • Additional symptoms for children > 2 years of age:  
o suprapubic, abdominal, or flank pain or tenderness OR 
o 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:  
o poor feeding OR 
o vomiting 
4) Only children who have been prescribed one of the four antibiotics for which a 
placebo is available will be eligible to participate. 
1 
TMP-SMX 
2 
Cefixime  
3 
Cefdinir 
4 
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). 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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5) Parental/guardian permission (informed consent) and if appropriate, child assent (if > 
seven years of age). 
 
6.2 
Subject Exclusion Criteria: Meets at Least One 
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, 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 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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11 
 
19) A child taking antibiotic prophylaxis for any reason.  
20) A child who has started Day 6 of the originally prescribed antibiotic treatment.  
 
6.3 
Recruitment Strategy 
Children will be recruited from three different sources: primary care sites, general 
pediatrics inpatient units and the emergency departments from the following locations: 
 
CHOP 
• 
CHOP’s Inpatient Service; 
• 
CHOP’s outpatient practice and urgent care network, which spans two states 
(Pennsylvania and New Jersey); 
• 
The CHOP Emergency Department; and 
• 
The General Pediatrics Inpatient Unit of CHOP. 
 
PITT 
• 
PITT’s Primary Care Centers; 
• 
PITT’s Practice Based Research Network, PittNet; 
• 
The PITT Emergency Department; and 
• 
The Inpatient Service at PITT. 
 
At both CHOP and PITT, SCOUT Study informational pamphlets will be prepared and 
distributed to all recruiting locations.  These materials will explain the study, the criteria 
for inclusion and exclusion, and the study procedures and timeframe.  These pamphlets 
can be used to familiarize primary care, ED and inpatient unit clinicians as well as 
subjects and families with the goals of the study.  In addition, to further aid recruitment, a 
study webpage will be available for additional information for clinicians and subject 
families. 
 
 
6.4 Treatment Assignment Procedures 
 
6.4.1 Randomization Procedures 
The SCOUT Study is a randomized, double-blind, placebo-controlled clinical trial.  
After a potential subject has been determined to meet eligibility criteria, the subject will 
be given a random treatment assignment of study product to either short-course or 
standard-of-care therapy.  Randomization will be done using fixed blocks of size four. 
Subjects will be stratified (within site) by febrile/non-febrile condition when originally 
diagnosed and antibiotic prescribed at initiation of therapy. That is, separate 
randomization sequences will be generated for each site for each of eight strata defined 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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by febrile/non-febrile condition and the four initially prescribed possible antibiotics.  
Treatment kits will be pre-packaged and randomized to active or placebo in a 1:1 ratio.  
Subjects initially prescribed cefdinir will be randomized to either cefixime or cefixime 
placebo. 
The SCOUT Study will employ WesTraxTM an interactive voice response (IVR) system 
to randomize subjects. This system uses the telephone as a means to input data. Pre-
recorded prompts are played listing the various options available to the user or 
requesting responses to particular questions. Data are entered using the telephone 
touch-tone keypad and are written to the underlying databases. The Study Nurse/Nurse 
Practitioner/Physician will randomize the subject based on the responses collected 
during the call into the system at the Enrollment Visit.   
The system security is enforced through the recognition of unique User ID and PIN 
numbers assigned to each system user. Each PIN number is associated with a list of 
system privileges.   
The Westat staff will train site personnel prior to study enrollment.  In addition, at the 
time of site activation, each user at the activated site will receive an instruction packet. 
User instructions are project-specific and the packet will contain the necessary 
instructions for the user's appropriate system access level.  
The WesTraxTM system will be available to all participating centers, 24 hours a day, 
seven days a week, with allowances for system maintenance operations, for the duration 
of study enrollment.  If users have questions about the system, a WesTrax coordinator is 
on call 24 hours a day, seven days a week and can be reached by dialing the Help 
Center.  All calls requiring action are recorded in a help desk database and metrics are 
readily available on calls for evaluation of additional training tool needs.  
 
6.4.2 Masking Procedures 
The study subjects and their families, investigators, and SCOUT Study team staff will 
remain blinded / masked to study treatment assignment (five more days of antibiotics 
therapy or five days of placebo) throughout the study. The subjects and their families, 
investigators, and SCOUT Study team staff will not be blinded to which one of the four 
antibiotics the subject was originally prescribed.  
The study products and placebo will be prepared centrally, by the UPENN 
Investigational Pharmacy, for both CHOP and PITT.  Only the Penn IDS Pharmacist will 
be aware of the study product bottle assignments. The staff at the medication storage 
areas at CHOP and PITT will be responsible for dispensing coded study products to 
preserve study blinding. For participants randomized to standard-of-care therapy, the 
pharmacy will provide the same medication prescribed to initially treat the UTI (NOTE: 
subjects initially prescribed cefdinir will be provided cefixime or cefixime placebo). The 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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Penn IDS pharmacy will prepare placebos that resemble the taste and consistency of 
the active antimicrobials. All study product kits will be packaged with an identical 
appearance. 
 
The UPENN Investigational Pharmacy will maintain study product accountability records 
for both CHOP and PITT. The study product kits will be similarly labeled with a numerical 
code that masks site investigators, site staff, parent(s)/guardian(s) and children to the 
formulation. In addition, the UPENN Investigational Pharmacy will place a two-part label 
on each of the study product kits. One part of the label will be removed and placed on 
the subject’s case report form or the medication accountability log and the second part of 
the label will remain on the bottle.  The Penn IDS pharmacist will be the only person to 
perform the unmasking if needed. 
During the consenting process it will be explained to the parents of any potential 
enrollees that the study product (treatment or placebo) that will be provided after day five 
may or may not taste exactly the same as the originally prescribed medication, and look 
and smell slightly different because it will be provided to the study pharmacy from a 
manufacturer which may be different than the manufacturer who provide the medication 
for the first five days. 
 
6.4.3 Reasons for Withdrawal 
The SCOUT protocol has been developed to minimize the number of participants lost to 
follow-up and reduce barriers to participation. The schedule of contacts is designed to 
facilitate participant retention through regular contact in a short timeframe.  
Participation in the SCOUT Study is voluntary. Subjects and their families can decide to 
discontinue participation at any time for any reason during the study by notifying study 
staff.   
In addition, the Investigators may discontinue participation for any subject at their 
discretion: if in their professional opinion, the subject’s health, safety, and/or well-being 
is threatened by continued participation in the study or they may withdraw those subjects 
that do not comply with the study, or to protect the subject for safety reasons or for 
administrative reasons. Subjects may also be discontinued from the study at the 
Investigator’s discretion for lack of adherence to study treatment or visit schedules, AEs, 
loss to follow-up or a protocol violation.     
Symptomatic subjects that develop a positive urine culture during the study period will 
not be considered withdrawn from the study, they will continue to be seen/contacted for 
any remaining study visits as part of safety follow-up.  These subjects will be treated 
outside this protocol by a physician not associated with the SCOUT Study per current 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
 _____________________________________________________________________________________________ 
 
14 
 
standard of care or if they prefer the parent(s)/legal guardian(s) can choose to have their 
child treated by their PCP/pediatrician. 
Subjects that develop a fever or worsening of symptoms after enrollment but prior to 
initiation of protocol treatment will be withdrawn from the study and considered entry 
failures.  These subjects will be treated outside this protocol by a physician not 
associated with the SCOUT Study per current standard of care or if they prefer the 
parent(s)/legal guardian(s) can choose to have their child treated by their 
PCP/pediatrician.   
It will be documented whether or not each subject completes the clinical study. If the 
Investigator becomes aware of any serious, related adverse events (AEs) after the 
subject completes or withdraws from the study, it will be recorded in the source 
documents and on the CRF. 
 
6.4.4 Handling of Withdrawals 
 
All withdrawals regardless of reason (whether the SCOUT PI or the parent removed the 
child from the study), will be followed-up by a phone call one week after their withdrawal 
to determine their status and if any medical follow up care was sought (in which case an 
MCN form will be completed). 
 
The Study Coordinator will collect data from the treating physician by completing the 
Medical Care Notification (MCN) Form.  
 
Symptomatic subjects that develop a positive urine culture will not be considered 
withdrawn from the study. They will continue to be seen/contacted for any remaining 
study visits as part of safety follow-up.  These subjects cannot be re-enrolled into this 
study.  For symptomatic subjects with positive urine culture and pyuria during the Day 6 -
10 period the study product will be discontinued. Symptomatic subjects with positive 
urine culture will be treated outside this protocol by a physician not associated with the 
SCOUT Study per current standard of care or if they prefer the parent(s)/legal 
guardian(s) can choose to have their child treated by their PCP/pediatrician. 
 
Subjects that withdraw or are withdrawn from the study prior to being evaluable for the 
primary outcome measure will be replaced. 
 
6.4.5 Termination of Study  
The National Institute of Allergy and Infectious Diseases (NIAID), the IRB, and the FDA 
reserve the right to discontinue the SCOUT Study at any time. Should the SCOUT Study 
be discontinued prior to completion, the study shall be completed, if medically 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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appropriate, for subjects who are enrolled in the study. In that event, each enrolled 
subject will be followed through the period outlined in the study.  


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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7 
STUDY INTERVENTION/STUDY PRODUCT 
7.1  
Study Product Description 
The UPENN School of Medicine will provide scientific expertise and will supply the study 
product and placebo through the Investigational Drug Service (IDS) of the Institute for 
Translational Medicine and Therapeutics. The study product will be prepared through the 
IDS for both CHOP and PITT. The CHOP and PITT Investigators and study team staff 
will be blinded to treatment arm assignment. 
 
For practical purposes, SCOUT will only enroll children whose physicians initiated 
therapy with one of the four most commonly used antimicrobials for UTI in children 
across the two participating clinical sites.   
These antibiotics are: 
• 
Trimethoprim- sulfamethoxazole (TMP-SMX) 
• 
Cefixime  
• 
Cefdinir1 
• 
Cephalexin 
 
In addition, the UPENN IDS will be compounding matching placebo products for each of 
the three study product antibiotics (those initially prescribed cefdinir are switched to 
bioequivalent cefixime).  These placebos will contain the following ingredients: 
• 
TMP-SMX placebo:  SyrSpend-SF ® Cherry, microcrystalline cellulose NF,, FD&C 
Yellow #6, carboxymethylcellulose NF, xanthan gum NF, citric acid NF, Tween 80®, 
sucrose NF, cherry syrup NF, FD&C Red #40, FD&C Yellow #6, Sucrose 
Octaacetate NF and Methylparaben NF. 
• 
Cefixime:  Sucrose granular USP, microcrystalline cellulose NF, xanthan gum NF, 
colloidal silicon dioxide NF, citric acid NF, and strawberry flavor. . 
• 
Cephalexin: Sucrose granular USP, microcrystalline cellulose NF, xanthan gum NF, 
colloidal silicon dioxide NF, citric acid NF, strawberry flavor, FD&C Red #40, and 
Allura Dye.  
                                                 
1 On occasion cefixime may not be available to the prescribing primary care physician.  Under such 
circumstances it is likely that cefdinir will be prescribed as an alternative agent to cefixime. The two 
antibiotics have therapeutic equivalence. If a child prescribed cefdinir is enrolled, they will be randomized 
to either five additional days of cefixime or the cefixime placebo. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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If the manufacturer of the active study product changes, only a change in color or flavor 
of the ingredients for the placebo may be acceptable in order to maintain the blind. 
7.1.1 Acquisition 
The UPenn IDS will purchase study products and place them into blinded treatment kits. 
Additional blinded treatment kits will be prepared which will include matching placebos 
that the IDS will manufacture for the study. Penn’s IDS will then transfer the treatment 
kits to the medication storage areas at CHOP and PITT. CHOP and PITT will be 
responsible for storing study products at their sites. They will oversee the preparation 
and dispensing of the three antibiotic (TMP-SMX, cefixime, and cephalexin) study 
product kits (those initially prescribed cefdinir are switched to bioequivalent cefixime) 
and placebos for CHOP and PITT as well as the maintenance of proper regulatory 
documentation. In addition, staff at the CHOP and PITT study product area will keep a 
log of all study products received and dispensed. 
7.1.2 Formulation, Packaging, and Labeling 
All study products will be dispensed as oral suspensions only.  
The formulations as obtained from the commercial manufacturers are as follows: 
• 
Trimethoprim- sulfamethoxazole (TMP-SMX); Oral suspension containing 200 
mg of sulfamethoxazole and 40 mg trimethoprim per 5 mL. 
• 
Cefixime (Suprax®):  Powder for oral suspension when reconstituted contains 
100 mg of cefixime as a trihydrate per 5 mL for smaller children or 200 mg of 
cefixime as a trihydrate per 5 mL for larger children. 
• 
Cephalexin: One package of oral suspension when reconstituted containing 
250mg of anhydrous cephalexin per 5mL for smaller children and two packages 
of oral suspension containing 250mg of anhydrous cephalexin per 5mL for larger 
children. 
Active cefixime and cephalexin will be transferred in their original commercial form into 
new containers strictly for blinding/masking purposes. These two medications will remain 
in un-constituted powder form until immediately before they are given to the subject. A 
separate smaller, clear TampAlert® jar will contain the pre-measured amount of sterile 
water that is needed to reconstitute the antibiotic powder. Trimethoprim-
sulfamethoxazole does not require reconstitution and will be given to the subject in the 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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manufacturer’s original packaging. For blinding purposes, bottles for the TMP-SMX 
placebos will be matched to the original’s manufacturer’s packaging.    
Each study product kit will be individually labeled with dosing instructions, recommended 
storage conditions, the do not use after date, kit number, “Investigational Use”, and that 
the agent should be kept out of reach of children. 
 
7.1.3 Study product Storage 
CHOP and PITT will store and oversee the preparation and dispensing of the three 
antibiotic (TMP-SMX, cefixime, and cephalexin) study product kits (those initially 
prescribed cefdinir are switched to bioequivalent cefixime) and placebos and the 
maintenance of proper regulatory documentation.  
At both sites, the study products will be stored in locked file cabinets in the study area. 
Only study personnel have keys for the study cabinet.  
All study products will be stored at room temperature at the study site prior to 
dispensing.  After dispensing, parents/caregivers will be instructed to: 
• 
refrigerate the: 
- 
cefixime suspension or placebo. 
- 
cephalexin suspension or placebo 
• 
keep at room temperature: 
- 
TMP-SMX or placebo 
7.2 
Dosage, Preparation and Administration of Study 
Intervention/Study product 
Description 
The Penn IDS will prepare study treatment kits containing sufficient study product for five 
days (days six -ten) plus a small overage.  Because the study products will be dosed 
based on body weight, the IDS will prepare two concentrations of cefixime so the site-
dispensing pharmacist can choose the study product bottle with the correct range to 
provide the required weight based volume dosage.  For cephalexin, one or two 
packages of study product will be provided depending on the weight of the child. The 
TMP-SMX packages will accommodate subjects of all weights, so there will only be one 
size of TMP-SMX packages prepared. The placebos will be prepared in identical 
containers and formulated to match their active antibiotics in taste, appearance and 
thickness. The Study Nurse/Nurse Practitioner/Physician will not be unblinded when they 
reconstitute the study product because the cefixime and cephalexin placebo powder 
matches the active powder.  
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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Treatment kits will be pre-packaged and randomized to active or placebo in a 1:1 ratio.  
The identity of each kit, including the antibiotic, size, active/placebo condition, as well as 
the site to which it has been shipped, will be registered by the IDS into the WesTrax™ 
system; this system will then randomize an individual kit to a subject, from the supply of 
kits which are available for use on-site.   
All three study products (those initially prescribed cefdinir are switched to bioequivalent 
cefixime or its matching placebo) and their matching placebos, will be packaged in 
bottles with child-resistant closures and a tamper-evident seal, which the Investigator, 
Nurse Practitioner or Study Nurse will break open at the time that the study product is 
dispensed.   
A treatment kit for five days for Days six - ten will contain: 
• 
One bottle of antibiotic or matching placebo; 
• 
A simple instruction sheet for the parent or caregiver, on which the daily dose is 
clearly marked; 
• 
An oral syringe and a measuring cup for proper administration; and 
• 
For cefixime, cephalexin or their respective placebo, a pre-measured container of 
sterile water which the pharmacist, physician, or nurse will use for reconstitution 
immediately prior to dispensing (for TMP-SMX this is not necessary because the 
commercial product is stable as a suspension already). 
• 
Larger children prescribed cephalexin will be given two kits of cephalexin or 
matching placebo. 
• 
Larger children prescribed cefixime will receive the higher concentration of cefixime 
or matching placebo. 
• 
Active TMP-SMX will be dispensed to the subject in the manufacturer’s original 
packaging. 
 
The SCOUT Physician, Study Nurse, or Nurse practitioner will reconstitute the study 
product prior to giving the study product to the parent/guardian. Active cefixime will be 
transferred in its original commercial form into new containers strictly for 
blinding/masking purposes.  Two concentrations will be prepared, a 50mL package of 
100mg/5mL suspension for smaller children (with 34mL of pre-measured sterile water in 
the same package) and a 50mL package of 200mg/5mL suspension for larger children 
(with 34mL of pre-measured sterile water in the same package).  The antibiotic is stable 
at room temperature and can also be refrigerated. For consistency, once mixed together, 
the label will identify that the product must be refrigerated and used within 14 days. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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Active cephalexin will be transferred in its original commercial form into new containers 
strictly for blinding/masking purposes.  A 200mL package of 250mg/5mL suspension 
(with132mL of pre-measured sterile water in the same package) will be provided to 
smaller children.  Larger children will receive two packages, each with equal volumes of 
sterile water.  The antibiotic is stable for 14 days refrigerated after reconstitution.  
 
Dosing and Administration 
Children will complete five days of their originally prescribed antibiotic and then take the 
study product according to Table 3 for the following five (5) days.  Subjects initially 
prescribed cefdinir will receive cefixime or cefixime placebo. 
 
 
 
Table 3 Oral Antibiotic Dosages 
Oral Antibiotic Dosage 
Trimethoprim-
Sulfamethoxazole* (TMP-SMX) 
8 mg/kg/day of Trimethoprim in 2 
divided doses,  
Max 160mg BID Trimethoprim 
Cefixime* 
8 mg/kg/day in 1 dose, 
Max 400 mg 
Cephalexin 
50mg/kg/day in 3 divided doses, 
* The placebo for each of the three antibiotics will be dosed by volume (those initially prescribed 
cefdinir are switched to bioequivalent cefixime) [49, 50]. 
 
Route of Administration  
All SCOUT Study products will be administered as an oral suspension by measuring cup 
or oral syringe. 
 
 
7.3 
Modification of Study Intervention/Study product for a 
Participant 
N/A. 
7.4 
Accountability Procedures for the Study Intervention/Study 
product(s) 
Study treatment kits will be registered by the Penn IDS into the WesTrax™ system at the 
time they are packed and shipped to the study storage sites.  Staff at each study product 
storage site will all have a log to record the study product bottles received as well as 
distributed. The sites will also use the WesTrax interactive voice response (IVR) system. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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21 
 
The WesTrax™ system has a supply management menu for the SCOUT Study with the 
following system menu options:  record the actual shipment date, confirm receipt of 
study product kit, request replacement, and request additional study product kits. 
Additionally, the UPENN Investigational Pharmacy will place a two-part label on the 
outside of each of the study product kits. One part of the label will remain on the outside 
of the kit.  A second label will be affixed to the study product bottle. The Penn IDS 
pharmacist will be the only person to perform the unmasking if needed. 
Westat, the SCOUT subcontractor for site monitoring, will monitor the study sites, 
storage areas, the pharmacy dispensing logs, as well as the documentation on study 
product preparation of the study product kits prior to enrollment as well as throughout 
enrollment to ensure accountability. 
7.5 
Assessment of Subject Compliance with Study 
Intervention/Study product  
At the Enrollment Visit, the parent(s) or guardian(s) will be given a subject medication 
diary. The Study Nurse/Nurse Practitioner/Physician will document the study product kit 
number, the date of the enrollment visit, and the date the study product was started. The 
Study Nurse/Nurse Practitioner/Physician will also explain the study product dosage 
instructions to the child’s caregiver(s): after completing five days of the originally 
prescribed antibiotic to then take the study product for five additional days (days six – 
ten). The Study Nurse/Nurse Practitioner/Physician will also explain how to use the 
medication diary to report the daily dose, the date, the time the study product was taken 
and the date that the study product was stopped. The Study Nurse/Nurse 
Practitioner/Physician will also explain how important it is to adhere to the instructions to 
complete the first five days of the originally prescribed antibiotic and then on days six – 
10 to take the study product. The Study Nurse/Nurse Practitioner/Physician will collect 
the subject’s medication diary and study product bottle at the Test of Cure Post-
Treatment Visit on Day 11 - 14.  
Dose Adjustments/Modifications/Delays  
Subject families will be told that if the child has missed one dose of antibiotic, they 
should not double the next dose. Instead, they should take the missed dose as 
prescribed as soon as they remember. At the Enrollment Visit, the Study Nurse/Nurse 
Practitioner/Physician  will provide the child’s parent(s)/legal guardian(s) with a study 
medication diary to record the day, time, and dose taken, missed doses, reason dose 
was missed (e.g. forgot to take dose, vomiting after taking study product) to help them to 
help with adherence and compliance. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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7.6 
Concomitant Medications/Treatments 
All concomitant prescription medications taken anytime during study participation will be 
reported on the case report forms (CRFs). All concomitant medications will be recorded 
from the Enrollment Visit (Day 2 – 6) through the end of the follow-up phone call on Day 
38-44. The concomitant medication form will be completed if the subject’s parent(s)/legal 
guardian(s) mentions that there are any other medications being taken at any point 
during the study period. The dates of administration, dosage, and reason for use will 
also be recorded. For this protocol, a prescription medication is defined as a medication 
that can be prescribed only by a properly authorized/licensed clinician.  Medications to 
be reported in the CRF are concomitant prescription medications, over-the-counter 
medications and non-prescription medications taken at any time during study period.


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                                  
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 9/20/2018 
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8 
STUDY SCHEDULE 
Table 4 Study Schedule 
Study Procedure 
Day 2-5 
(Day 1 = 
Start of 
antibiotic 
treatment) 
Day 2-6 
(Prior to 
Taking Day 6 
prescribed 
antibiotic) 
 
Day 5-6 
(only for 
subjects 
enrolled 
on D2-4) 
Day 11 - 14 
( 1 – 4 days 
after 
completing 
the study 
product) 
Day 24 – 30 
(14 – 20 days 
after 
completing 
the study 
product) 
Day 38 - 44 
(28-34 days 
after 
discontinuati
on of study 
product) 
Day 4 – 44 
(Throughout 
SCOUT 
Study 
enrollment) 
Study Point of Contact 
Recruitment 
Call 
Enrollment 
Study Visit 
Follow-up 
Contact 
(phone, 
e-mail, 
etc.) 
Test of Cure 
Study Visit 
Outcome 
Assessment  
Visit 
Follow-Up 
Phone Call 
As Needed if 
symptomatic 
Recruitment  
x 
 
 
 
 
 
 
Request Study Participation 
 
x 
 
 
 
 
 
Verbal consent for screening 
x 
 
 
 
 
 
 
Written Informed Consent / 
Assent 
 
x 
 
 
 
 
 
Obtain/review Medical history 
 
x 
X 
 
 
 
 
 
Symptom Questionnaire 
x 
x 
 
x 
x 
x 
 
Randomization 
 
x 
 
 
 
 
 
Take Child’s Temperature 
 
x 
 
x 
x 
 
x 
Clinical Evaluation 
 
x 
 
x 
x 
 
x 
Assess for suprapubic, 
abdominal, or flank pain or 
tenderness 
 
x 
 
x 
x 
 
x 
Stool Sample** 
 
x 
 
x 
x 
 
 
Concomitant Medication Form 
 
x 
 
x 
x 
x 
x 
Medication Diary  
 
 
 
x 
 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                                  
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 9/20/2018 
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*If the Study Nurse is not able to collect a urine specimen at the TOC Visit for asymptomatic subjects, then an attempt will be made to collect a urine sample at the 
Outcome Assessment Visit. 
** A stool sample will not be collected at the unscheduled assessment visits. 
Urine Specimen for Urinalysis 
& Urine Culture  
 
 
 
x 
x* 
 
x 
Collect SAEs 
 
 
 
x 
x 
x 
x 
Report Intercurrent Illnesses 
or Symptoms 
 
x 
 
x 
x 
x 
x 
Verify afebrile and no 
worsening of symptoms since 
enrollment 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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8.1 
Recruitment and Preliminary Screening  
 
Day 1 (one day from start of prescribed antibiotics): Identify Potential Subjects. 
The primary care clinician affiliated with one of the two clinical trial centers identifies 
potential subjects and informs the eligible (symptomatic and urine culture positive UTI) 
child and their parent(s)/legal guardian(s) about the SCOUT Study, shares the SCOUT 
Study informational pamphlet and asks permission for the child’s family to be contacted 
by the study staff. An EHR prompt will remind clinicians to speak to the family about the 
study. If the family is interested in obtaining additional information or enrolling their child, 
the primary care clinician will share their contact information with the SCOUT Study 
Coordinator. The EHR prompt will also allow the clinician to alert study staff if a family 
should not be contacted about the study or has declined participation. Unless the Study 
Coordinator is instructed by the treating clinician to refrain from contacting the patient’s 
parent/guardian, he/she will contact the eligible child’s parent(s)/legal guardian(s) about 
the SCOUT Study.  However, if the study team does receive a report that the 
parent/guardian has declined to be contacted, no contact will be made by the SCOUT 
research team.  
 
At CHOP an IRB approved recruitment email blast will be used to aid in reaching 
potential subjects seen at the outpatient and urgent care network practices in both 
Pennsylvania and New Jersey. An honest broker will send the emails utilizing a 
participant recruitment service based solely on the existence of a urine culture order in 
the potential subjects’ medical record.  The email contains a letter from the Principal 
Investigator at CHOP explaining the details of the study and contact information for the 
primary Study Coordinator. Parents(s) and legal guardian(s) will have the opportunity to 
reach out to a study specific email address as well if they are interested in participating 
in the study or determining if their child is eligible. 
 
 
Day 2 - 5: Preliminary Screening and Recruiting Period 
 
The Study Coordinator will preliminarily screen2 a referred subject by reviewing their 
microbiology and hematology lab report to confirm a UTI and review their medical health 
record for study eligibility (fever and/or urinary symptoms, pyuria, positive urine culture 
and susceptibility results, and medical history).  
If no exclusion criteria are met, the Study Coordinator will attempt to contact the 
parent(s)/guardian(s) by phone. The Study Coordinator will read an IRB approved 
telephone script, and obtain verbal consent from the parent(s)/guardian(s) for screening 
before proceeding with a brief symptom questionnaire to determine whether the child 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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26 
 
experienced any UTI symptoms prior to the diagnosis that were not captured in the EHR.  
Once obtained, the verbal consent will be documented as per local institutional policy. 
The Study Coordinator will also explain the study protocol and describes the 
inclusion/exclusion criteria. The Study Coordinator will answer any questions and 
concerns the parent/guardian may have. 
If it appears that a patient may be eligible based on hematology results and medical 
record review, the Study Coordinator may contact the parent(s)/guardian(s) by phone 
before urine culture results have been received. The Study Coordinator will call the 
parent(s)/legal guardian(s) again once culture results are received to inform them of their 
child’s eligibility status. Patients with cultures that do not meet inclusion criteria will be 
instructed to continue with initially prescribed antibiotic unless otherwise advised by the 
prescribing clinician.  
 
If the patient has returned a positive culture, and the parent(s)/legal guardian(s) are still 
interested and believe their child meets the study eligibility criteria, the Study 
Coordinator will schedule the Enrollment Visit for a time before the child starts the sixth 
day of the initial antibiotic therapy. The enrollment visit may proceed even if urine culture 
sensitivities are still pending at the time of the visit. However, if final sensitivities show 
that the organism is resistant to the initially prescribed antibiotic, the subject is no longer 
eligible and should be excluded (or discontinued if the child was already enrolled). Staff 
will instruct the parent(s)/guardian(s) to continue with the initially prescribed antibiotic 
unless otherwise advised by the prescribing clinician. 
 
If needed, study staff may contact the parent/guardian again just before the Enrollment 
Visit to confirm the appointment time and location and to ask whether the child is still 
experiencing UTI symptoms. If the parent/guardian reports that symptoms are still 
present, the visit will be rescheduled for a later day (if prior to day 6) or the parent will be 
instructed to continue administration of original antibiotic as instructed by the treating 
clinician.  
8.2 
Enrollment Visit (Day 2-6 from start of prescribed antibiotics) 
Prior to taking the sixth day of prescribed treatment  
The Study Nurse/Nurse Practitioner/Physician will discuss the SCOUT Study, the goal, 
the study procedures and risks with the parent(s)/legal guardian(s); answer any 
questions and address any concerns that they have; have the parent(s) or guardian(s) 
sign the informed consent form and the child sign the assent form (if > seven years of 
age and enrolled at CHOP) if applicable prior to any study procedures being performed. 
Study Nurses/Nurse Practitioners/Physicians will also administer the eligibility 
questionnaire; administer a symptom questionnaire to confirm by history clinical 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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improvement (afebrile within 24 hours and asymptomatic [absence of dysuria in all 
children; absence of suprapubic, abdominal or flank pain, urinary urgency, frequency, 
hesitancy, dysuria in children >2 years and absence of poor feeding or vomiting in 
children >2 months to 2 years]); take the child’s temperature; and perform a targeted 
pain assessment for any suprapubic, abdominal, or flank pain/tenderness. In addition, a 
baseline stool sample will be collected and concomitant medications will be reviewed. 
The written consent and assent documents, acquired from subject’s parent(s) or legal 
guardian(s) and subject (if age seven or older and enrolled at CHOP) before any study 
procedures are performed and the child is enrolled in the study, will describe potential 
risks and benefits of study participation as well as the responsibilities of the study 
participants, parent(s) or legal guardian(s), and study investigators. This assent 
document will be written in language understandable to the child (age seven or older).  
At the Enrollment Visit, after a potential subject has met the study eligibility criteria, 
including exhibiting clinical improvement (afebrile and asymptomatic), the child will be 
given a random treatment assignment to either short-course or standard-of-care therapy.  
Subjects will be randomized based on the responses of the Study Nurse/Nurse 
Practitioner or Physician to the WesTraxTM interactive voice response (IVR) system.  The 
system will stratify randomization based on whether:  
(1) The UTI was originally associated with fever and  
(2) The antibiotic prescribed at initiation of therapy.   
If the Enrollment Visit occurs at any time prior to completion of the day 5 dosing of 
prescribed antibiotic treatment, the child’s parent(s)/legal guardian(s) will be advised to 
complete their originally prescribed medication through day five.  The subject would start 
study product on Day 6 and continue through Day 10.  For these subjects enrolled prior 
to Day 5, confirmation from the parents will be obtained on Day 5 or Day 6 (prior to 
taking the first dose of SCOUT therapy on Day 6) that the subjects remain afebrile and 
have not had worsening of symptoms.  Any volunteer that develops a fever or worsening 
symptoms prior to initiating study treatment will be considered an entry failure.  If the 
Enrollment Visit occurs on Day 6, the Study Coordinator will clearly explain that the 
Enrollment Visit can only occur on Day 6 of antibiotic treatment if the child has not yet 
started the Day 6 dose of the initially prescribed antibiotics.  The Study Nurse/Nurse 
Practitioner/Physician will confirm (at the Enrollment Visit) that the child has not yet 
started their Day 6 dose of prescribed antibiotics prior to enrolling them through the 
“Enrollment Visit Case Report Form.’ 
The Study Nurse/Nurse Practitioner/Physician will review the contents of the study 
product kit with the child’s family, review the need to complete the study product at the 
dose and frequency indicated and teach them how to complete the medication diary to 
document adherence.   


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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Parents will be educated at the time of their child’s enrollment in the study about the 
potential sequelae of untreated UTI and the benefits of prompt and adequate treatment. 
They will be instructed to (1) contact primary care providers and study personnel in the 
event of intercurrent febrile illness, (2) have their child evaluated within 36 hours by a 
SCOUT study physician or the child’s primary care provider and (3) have a urine sample 
obtained to evaluate for the presence of UTI. The study nurses, nurse practitioners and 
the investigators at each site will be available on a 24-hour basis, through a study-
dedicated cellular phone. 
Stool specimens will be collected either by inoculation of a sterile dacron-tipped swab 
into stool in a diaper, or by insertion of a swab into the distal rectum (similar to obtaining 
a rectal temperature) where it will be held in this position for five seconds. 
 
For each subject at CHOP who agrees to participate in the Microbiome pilot study, an 
additional perirectal swab and anal swab will be collected. The additional swabs will be 
used to determine the composition of the subjects’ microbiome. The anal swab will be 
collected by brushing the swab back and forth five times against the skin just outside of 
the rectum. For subjects in diapers, a third swab will be collected from the stool in the 
diaper if one is available.  
Primary care providers will be notified of their patient’s participation in the study via 
telephone, letter, email or electronic health record message.  
CHOP Study Visits 
Parents of children recruited at CHOP will be given the option of coming to the Wood 
building at CHOP, meeting the Study Nurse/Nurse Practitioner/Physician at their local 
primary care practice site, or having a study staff conduct the study visit in their home.  
PITT Study Visits 
Children recruited at Children’s Hospital of Pittsburgh will have the study visit conducted 
at the Primary Care Center of Children’s Hospital of Pittsburgh or at one of the 
community offices where PITTnet personnel are available. 
Subjects will be given appointments at the time of study entry for the Day 11 – 14 Test of 
Cure Visit and the Day 24 – 30 Outcome Assessment Visit. The Study Nurse/Nurse 
Practitioner/Physician will explain that during each study visit, the Study Nurse/Nurse 
Practitioner/Physician will ask a specific series of questions to determine the resolution 
of UTI related symptoms.  These study visits will consist of a verbal clinical assessment 
(symptom questionnaire) and a targeted pain assessment.  For subjects enrolled before 
Day 5, the Study Nurse/Nurse Practitioner/Physician will explain that verification will be 
obtained on Day 5 or prior to taking the first dose of SCOUT therapy on Day 6 that the 
subject remains afebrile and with no worsening of symptoms.  Any subject that develops 
a fever or worsening of symptoms (prior to starting study product) will be withdrawn from 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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29 
 
the study and considered an entry failure.  These subjects will be treated outside this 
protocol by a physician not associated with the SCOUT Study per current standard of 
care or if they prefer the parent(s)/legal guardian(s) can choose to have their child 
treated by their PCP/pediatrician.   
Days Six -Ten (While on the study product: continued antibiotic or placebo): 
During the five days (days six – ten) that the subject is taking the study product, if the 
child presents any UTI symptoms (fever or dysuria for all children; absence of 
suprapubic, abdominal, or flank pain or tenderness; urinary urgency or frequency for 
children > 2 years of age; poor feeding or vomiting for children ≥ 2 months to 2 years of 
age) or if the child experiences diarrhea or develops a rash (as a reaction to the 
antibiotic) the parent or guardian will be instructed to notify the Study Nurse, Nurse 
Practitioner, Physician  or Study Coordinator. They will be seen within 36 hours by one 
of the SCOUT Study physicians or if they prefer the parent(s)/legal guardian(s) can 
choose to have their child treated by their PCP/pediatrician.  All symptomatic children 
will have a urine sample taken for urinalysis and culture. If a visit with SCOUT Study 
physicians cannot be scheduled, urinalysis and culture results from the PCP visit can be 
used for study endpoints.  If the urinalysis is positive for pyuria and the urine culture is 
positive, the symptomatic child will stop the study product, and will be treated outside 
this protocol by a physician not associated with the SCOUT Study per current standard 
of care or if they prefer the parent(s)/legal guardian(s) can choose to have their child 
treated by their PCP/pediatrician. If the families prefer to see their PCP or pediatrician, 
the Study Nurse, Nurse Practitioner, Physician and/or Study Coordinator will help to 
facilitate the follow- up appointment. The Study Coordinator will share all pertinent 
information related to the study with the physician.  Subjects who develop adverse 
reactions to study product will discontinue the study product.  
8.3 
Test of Cure (TOC) Post Treatment Visit  
Day 11 – 14 (one – four days after completing the study product) 
Subjects will return for a follow-up visit two – four days after completing the study 
product. At this follow-up visit, a Study Nurse/Nurse Practitioner/Physician will perform 
assessments of the subjects. Using a standardized interview form (symptom 
questionnaire), the subjects and/or their parent(s) or legal guardians will be asked to 
provide a subjective evaluation of the presence or absence of UTI symptoms and 
possible side effects of the antibiotic like diarrhea or a rash. Parent(s) or legal 
guardian(s) will also be asked to report any inter-current illnesses (e.g., upper respiratory 
infection, pharyngitis, otitis media, sinusitis), the name and duration of concomitant 
therapy, and potential side effects of study product. They will also be asked if the subject 
sought medical care for possible recurrence of UTI, the records of the encounter 
including microbiology culture results will be obtained so the SCOUT Study physician, 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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30 
 
nurse practitioner or nurse can follow up with the child’s parent(s)/legal guardian(s) and 
PCP. The Study Nurse/Nurse Practitioner/Physician will collect a second stool sample, 
the medication diary and the study product bottle. Subjects at CHOP who agree to the 
Microbiome sub-study will have additional peri-rectal, anal, and stool swabs collected, if 
applicable. The subject’s temperature will also be taken and the child will be assessed 
for any suprapubic, abdominal, or flank pain or tenderness. In addition, the Nurse will 
collect a urine sample for urinalysis and culture from all subjects. The Study 
Nurse/Nurse Practitioner/Physician will use the bag technique on asymptomatic infants 
and young children (before they are toilet trained) and the clean catch technique for 
older toilet trained children.  For symptomatic infants and young children a urine sample 
will be obtained using the clean catch technique (or catheterize if unable to capture with 
clean catch).   
If the subject is symptomatic and the urine culture is positive, the child will be treated 
outside this protocol by a physician not associated with the SCOUT Study per current 
standard of care or if they prefer the parent(s)/legal guardian(s) can choose to have their 
child treated by their PCP/pediatrician (See Table 5 for details on which scenarios 
require referrals to non-SCOUT physicians at or after the Test of Cure Visit.).  Subjects 
that are asymptomatic with a positive urine culture (specimen collected via bag) will 
continue with the study as planned. NOTE: Subjects that are diagnosed with a culture 
positive UTI prior to the TOC Visit (between Day 6 and Day 11-14 TOC Visit) will have 
the above listed procedures performed during the Interim Visit for reoccurrence of 
symptoms excluding the stool specimen collection.  Data obtained from this visit will 
apply towards the primary endpoint.  They will not have to return for the TOC visit.     


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                                  
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 9/20/2018 
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31 
 
Table 5:  SCOUT Study Referrals to outside physicians at TOC or later. 
 
Scenario 
UTI 
Symptomology 
Urine 
culture 
result 
Pyuria 
present 
 
Follow-up required: 
Repeat urine culture result/outcome 
Symp 
Asymp1 
+ 
- 
Yes 
NO 
1 
X 
 
X 
 
X 
 
Refer to non-SCOUT 
physician 
 
 
2 
X 
 
X 
 
 
X 
Refer to non-SCOUT 
physician 
 
 
3 
X 
 
 
X 
X 
 
Follow-up required.   
Contact subject in 24-
48 hrs.  Perform repeat 
urine culture if still 
symptomatic. If 
asymptomatic, 
continue with study as 
planned 
+ 
 
Refer to non-
SCOUT physician 
- 
 
Continue with 
study as planned, 
monitoring closely 
4 
X 
 
 
X 
 
X 
Follow-up required.  
Contact subject in 24-
48 hrs - if still 
symptomatic - perform 
repeat culture. If 
asymptomatic, 
continue with study as 
planned 
+ 
 
Refer to non-
SCOUT physician 
- 
 
Continue with 
study as planned, 
monitoring closely 
5 
 
X 
X 
 
X 
 
Asymptomatic 
Bacteriuria, continue 
with study as planned 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                                  
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 9/20/2018 
 _____________________________________________________________________________________________ 
 
32 
 
6 
 
X 
X 
 
 
X 
Asymptomatic 
Bacteriuria, continue 
with study as planned 
 
 
7 
 
X 
 
X 
X 
 
Continue with study as 
planned 
 
 
8 
 
X 
 
X 
 
X 
Continue with study as 
planned 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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33 
 
Also, for asymptomatic subjects if a urine sample cannot be obtained at this visit, 
another attempt to obtain a urine sample will be made at the Day 24-30 Outcome 
Assessment Visit.   
 
  
8.4 
Outcome Assessment Visit 
Day 24 - 30 (14 – 20 days after completing the study product):  
The Study Nurse/Nurse Practitioner/Physician will administer the symptom 
questionnaire, take the child’s temperature, and collect a third stool sample.  Subjects at 
CHOP who agree to the Microbiome sub-study will have additional peri-rectal, anal, and 
stool swabs collected, if applicable. In addition, the child will be assessed for any 
suprapubic, abdominal, or flank pain or tenderness. The purpose of this visit is to assess 
for recurrent infections (relapse or reinfection).  
If applicable, for asymptomatic subjects for whom no urine sample could be obtained at 
the TOC visit another attempt will be made to obtain a urine sample at this visit.  This 
sample is taken as a safety measure.  
If the subject is symptomatic and the urine culture is positive, the child will be treated 
outside this protocol by a physician not associated with the SCOUT Study per current 
standard of care or if they prefer the parent(s)/legal guardian(s) can choose to have their 
child treated by their PCP/pediatrician. If the families prefer to see their PCP or 
pediatrician, the Study Nurse, Nurse Practitioner, Physician and/or Study Coordinator 
will help to facilitate the follow up appointment. The Study Coordinator will share all 
pertinent information related to the study with the physician. 
All of the above procedures will be performed for subjects that were categorized as 
treatment failures or diagnosed as having asymptomatic bacteriuria prior to this visit. 
These procedures include stool specimen collection. 
 
8.5 
Follow-Up Phone Call  
Day 38 – 44 (28-34 days after completing the study product): 
The Study Nurse, Nurse Practitioner, Physician or Study Coordinator will follow up by 
phone with the subject’s parent(s)/legal guardian(s) to administer the symptom 
questionnaire. The purpose of this call is safety and to evaluate for the presence or 
absence of a new urinary tract infection.   
Using a standardized interview form (symptom questionnaire), the subjects and/or their 
parent(s) or legal guardians will be asked to provide a subjective evaluation of the 
presence or absence of UTI symptoms. Parent(s) or legal guardian(s) will also be asked 
to report any inter-current illnesses (e.g., upper respiratory infection, pharyngitis, otitis 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
 _____________________________________________________________________________________________ 
 
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34 
 
media, sinusitis), the name and duration of concomitant therapy, and potential side 
effects of study product. If the subject sought medical care for possible recurrence of 
UTI, the records of the encounter including microbiology culture results will be obtained 
so the SCOUT Study physician, nurse practitioner or nurse can follow up with the child’s 
parent(s)/legal guardian(s) and PCP.  Subjects that were categorized as treatment 
failures prior to this visit will be asked about the presence or absence of UTI symptoms 
and the follow-up treatment received.  
All children that report symptoms associated with UTI during the phone call will have a 
visit scheduled to collect a urine sample for urinalysis and culture, and will be treated 
outside this protocol by a physician not associated with the SCOUT Study per current 
standard of care or if they prefer the parent(s)/legal guardian(s) can choose to have their 
child treated by their PCP/pediatrician.  If the families prefer to see their PCP or 
pediatrician, the Study Nurse, Nurse Practitioner, Physician and/or Study Coordinator 
will help to facilitate the follow up appointment if needed. The Study Coordinator will 
share all pertinent information related to the study with the physician.  A SCOUT Study 
physician, nurse practitioner or nurse will follow up with the PCP/pediatrician on the 
child’s status.    
 
 
8.6 
Early Termination Visit 
Subjects that choose to withdraw or are withdrawn by the PI prior to the Day 11-14 TOC 
visit will be asked to be evaluated for UTI symptoms and possible side effects of the 
antibiotic like diarrhea or a rash. Parent(s) or legal guardian(s) will also be asked to 
report any inter-current illnesses (e.g., upper respiratory infection, pharyngitis, otitis 
media, sinusitis), the name and duration of concomitant therapy, and potential side 
effects of study product. They will also be asked if the child sought medical care for a 
possible recurrence of UTI.  However, no urine or stool sample will be obtained.  If the 
subject presents with UTI symptoms at the termination visit, the SCOUT PI will inform 
their PCP/pediatrician and share all pertinent information related to the study and urge 
the parent(s)/legal guardian(s) to follow-up with their PCP/pediatrician. 
Study staff will request that subjects that choose to withdraw or are withdrawn any time 
after the TOC visit be contacted for the Day 38-44 follow-up phone call for assessment 
of adverse events.   


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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35 
 
9 
 STUDY PROCEDURES/EVALUATIONS 
9.1 
Clinical Evaluations 
 
Subjects will be seen by a clinician for three study visits:   
1. Enrollment Visit (Day 2 - 6) 
2. Test of Cure Visit (Day 11 - 14) 
3. Outcome Assessment Visit (Day 24 - 30) 
 
Subjects enrolled prior to Day 5 of their prescribed medication will be verified as afebrile 
and with no worsening of conditions on Day 5 or prior to receiving the first dose of 
SCOUT therapy on Day 6.  In addition, subjects will be contacted by phone at the end of 
the study period on the Follow-up Phone Call (Day 38 - 44).   
 
Throughout the study, the study nurse, nurse practitioner, MD, PA, DO or DDS listed on 
the form FDA 1572 may perform and document study assessments and confirm 
eligibility. Only clinical personnel licensed to perform pain assessments will complete 
these procedures.   
 
A diagnosis of clinical and microbiological failure as well as asymptomatic bacteriuria will 
only be made by a MD, PA, DO, DDS or CRNP listed on the form FDA 1572. Clinical 
evaluations at each visit will be as follows: 
Day 2-6 (anytime after initiation of antibiotic treatment but prior to starting the sixth day 
of study treatment):  
To confirm eligibility including clinical improvement (afebrile and asymptomatic) a pain 
assessment will be performed checking for any suprapubic, abdominal, or flank pain or 
tenderness.  In addition, the temperature will be taken and a base line stool sample will 
be obtained.  If a study RN receives a report of a UTI symptom at a study visit, he/she 
will inform the parent/guardian that the child should be seen by a clinician licensed to 
diagnose and treat the UTI. If this occurs at the enrollment visit, the child will be 
excluded from the study and will be referred back to the PCP who initially treated the 
child.  
 
Confirmation is obtained by study staff that the subject remains afebrile with no 
worsening of symptoms on Day 5-6 (prior to taking the first dose of SCOUT therapy on 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
 _____________________________________________________________________________________________ 
 
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36 
 
Day 6) for subjects enrolled prior to Day 5.  Any volunteer that develops a fever or 
worsening of symptoms will be withdrawn from the study and considered an entry failure.  
These subjects will be treated outside this protocol by a physician not associated with 
the SCOUT Study per current standard of care or if they prefer the parent(s)/legal 
guardian(s) can choose to have their child treated by their PCP/pediatrician. 
 
 
 
Day 11 -14 Test of Cure Post Treatment Visit (one – four days after completing the  
 
 
 study product):  
The child will be clinically assessed for the presence of UTI symptoms and a urine 
specimen will be collected for test of cure. In addition, a pain assessment will be 
performed checking for any suprapubic, abdominal, or flank pain or tenderness and the 
child’s temperature will be taken and a stool sample will be obtained. If a study RN 
receives a report of a UTI symptom at the Test of Cure visit, he/she will inform the 
parent/guardian that the child should be seen by a clinician licensed to diagnose and 
treat the UTI. The RN will document the symptom on the appropriate case report form 
and will contact a study physician to arrange follow-up visit. 
 
  
Day 24 - 30 Outcome Assessment Visit (14-20 days following study product completion):  
The child will be clinically assessed for the presence of UTI symptoms. In addition, a 
targeted pain assessment will be performed checking for any suprapubic, abdominal, or 
flank pain or tenderness and the child’s temperature will be taken and a stool sample will 
be obtained. If a urine specimen could not be collected at the Day 11 – 14 TOC Visit for 
asymptomatic subjects, another attempt to collect a urine sample at this visit will be 
made. If a study RN receives a report of a UTI symptom at the Outcome Assessment 
visit, he/she will inform the parent/guardian that the child should be seen by a clinician 
licensed to diagnose and treat the UTI. The RN will document the symptom on the 
appropriate case report form and will contact a study physician to arrange follow-up visit. 
 
Day 38 - 44 Follow-up Phone Call (28-34 days after completing the study product): 
Subjects will be asked regarding presence or absence of UTI symptoms, if they sought 
medical care for possible recurrence of UTI, and to report any inter-current illnesses. 
9.2 
Laboratory Evaluations 
The Infectious Disease Research Laboratory (IDRL) at Children’s Hospital of Pittsburgh 
(PITT) of the University of Pittsburgh Medical Center will serve as the central 
microbiology core laboratory for the stool sample analysis for both clinical trial centers. 
The CHOP and PITT microbiology and hematology laboratories will analyze the urine 
culture and urinalysis specimens respectively. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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37 
 
9.2.1 
Clinical Laboratory Evaluations 
Stool samples 
Upon arrival in the IDRL, stool swabs will be initially inoculated onto Maconkey agar.  All 
isolates that grow on Maconkey agar will have identification confirmed using API 
identification strips. Isolates confirmed to be E. coli or K. pneumoniae will undergo 
further evaluation and will be subcultured onto 5% sheep blood agar.  Isolates of E. coli 
will undergo screening for the presence of antimicrobial resistance against amoxicillin, 
amoxicillin- clavulanate, TMP-SMX using Kirby-Bauer Disk diffusion according to 
published CLSI guidelines (ref). Isolates of K. pneumoniae will undergo screening for the 
presence of antimicrobial resistance against amoxicillin- clavulanate and TMP-SMX 
using Kirby-Bauer Disk diffusion according to published CLSI guidelines (ref). Isolates of 
either pathogen found to have a zone of inhibition consistent with them being non-
susceptible (either intermediate or resistant) will undergo MIC determination against the 
relevant antimicrobial agent(s) using the E-test (bioMerieux, Durham, NC). 
Screening for third generation cephalosporin resistance for all isolates of E. coli and K. 
pneumoniae will be done using selective media: Maconkey agar containing subinhibitory 
concentrations of ceftazidime. Isolates of E. coli or K. pneumoniae that have grown on 
this selective media will be further tested to determine their MIC to ceftazidime using the 
E-test. In addition to determination of the MIC, isolates of either of these pathogens that 
grow on the ceftazidime-containing selective media will be screened for the presence of 
ESBL production using the ESBL strip ceftazidime / ceftazidime + clavulanic acid (AB 
BioDisk). Isolates of E. coli or K. pneumoniae that are resistant to any of the four (those 
initially prescribed cefdinir are switched to bioequivalent cefixime or its matching 
placebo) antimicrobials (or that demonstrate ESBL production by double disk synergy 
test) will be frozen at -70 C for future evaluation including determination of the 
mechanism of resistance and epidemiological relationships. 
Each isolate of E. coli and K. pneumoniae will be defined as demonstrating an MIC that 
is susceptible, intermediate (where appropriate) or resistant for the specific antibiotic. 
For TMP-SMX, the breakpoint for susceptible is < 2 ug/ml TMP and < 38 ug/ml SMX 
while resistance is > 4 ug/ml TMP and > 76 ug/ml SMX.   For Amoxicillin-Clavulanate, 
susceptible is < 8/4 ug/ml, intermediate is 16/8 ug/ml and resistant is > 32/16 ug/ml.  
Although a similar approach could be offered for ceftazidime resistance in E. coli, most 
experts would consider all ESBL-containing E. coli to be resistant to ceftazidime 
regardless of the MIC.  Accordingly, we would argue that this secondary endpoint would 
be based on the presence or absence of ESBL as determined by the double-disk 
diffusion test for synergy between clavulanic acid and both ceftazidime and cefotaxime. 
An increase of > 5 mm in zone diameter for either antimicrobial agent tested in 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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combination with clavulanic acid compared with its zone when tested alone will be 
confirmation of the ESBL phenotype. 
For each enrolled research subject, the second stool or perirectal swab will also be 
utilized to perform additional screening for the presence of carbapenem resistant 
enterobacteriaceae. These second swab specimens will be streaked on to Carbapenem 
resistant Enterobacteriaceae agar (Hardy's Diagnostic Company). This media selects 
against growth of Gram positive bacteria and selects for growth of Gram negative 
bacteria with decreased susceptibility to carbapenems. The carbapenem resistant 
Enterobacteriaceae plates will be incubated in ambient air at 37ºC for 24 hours. Per the 
manufacturer's recommendation, Carbapenem resistant Enterobacteriaceae plates with 
no growth at 24 hours will be considered negative. Colonies that grow at 24 hours are 
presumed to be Gram negative bacteria and will undergo subsequent formal 
identification (using API E20 test kits) and susceptibility testing against meropenem, 
imipemen and ertapenem by E-test in accordance with guidelines from the Clinical 
Laboratories Standards Institute to determine presence or absence of carbapenem 
resistance. Rates of colonization by carbapenem-resistant Enterobacteriaceae (overall 
and for specific pathogens) will be determined. 
Urine samples 
The site’s microbiology and hematology labs will run tests on the urine as per standard 
CHOP and PITT procedures for a urine culture and urinalysis. These standards include 
the following differences in procedures: 
• 
Cultures will be checked for growth after  
o CHOP: 20-24 hours.  
o PITT: at least 18 hours. 
• 
Cultures are reported as “No growth” if 
o CHOP:  < 102 CFU/ml      
o PITT: there is no growth      
• 
Cultures will be inoculated with: 
o CHOP: blue (10µl) loops or green (1µl) loops 
o PITT: green (1µl) loops only 
• 
Individual colony counts will be reported for 
o CHOP: up to 3 organisms 
o PITT: up to 2 organisms:  
▪ 
If the two organisms are between 104 – 105 CFU/ml, ID and 
sensitivities are performed on each of them 
▪ 
If one is >104 CFU/ml and one is <104 CFU/ml, ID and sensitivities 
performed on the former and the latter is only described 
 Routine Evaluations 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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When clinically appropriate, routine laboratory measurements will also be performed 
according to the medical judgment of the investigators. 
 
9.2.2 
Special Assays or Procedures 
N/A 
 
9.2.3 
Specimen Preparation, Handling, and Shipping 
9.2.3.1 
Instructions for Specimen Preparation, Handling, and Storage 
Urine 
A urine specimen will be collected for urinalysis and culture at the Test of Cure visit. If a 
urine specimen is not able to be collected for asymptomatic subjects, the Study 
Nurse/Nurse Practitioner/Physician will attempt to collect a urine specimen at the 
Outcome Assessment Visit. A urine specimen will also be collected at any time during 
study enrollment if the child presents with UTI symptoms.  
Urine specimens will be collected by various methods depending on the age of the 
subject and the symptoms, as detailed in the table below. 
 
 
Table 6: Urine Specimen Collection by Age and Symptom Status 
Child Age and Status 
Method of Urine Collection 
Asymptomatic infants and young children 
Bag technique 
Asymptomatic toilet trained children 
Clean catch technique 
Symptomatic infants and young children 
Clean catch or catheterize 
Symptomatic toilet trained children 
Clean catch technique 
Urine specimens for local analysis will be delivered to the site’s microbiology laboratory 
within one hour of collection, or kept in a box containing ice cubes, or refrigerated until 
delivered to the lab.   
If an asymptomatic child does not urinate during the allotted TOC Visit time period, the 
Nurse will request additional time from the parents, but if they are not able to have the 
study visit continue, then the nurse will attempt to collect a urine specimen at the 
Outcome Assessment Visit on Day 24 - 30. 
 
Stool samples 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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A stool specimen to determine antimicrobial resistance will be collected at all three study 
visits. Stool specimens will be collected either by inoculation of a sterile dacron-tipped 
swab into stool in a diaper, or by insertion of a swab into the distal rectum (similar to 
obtaining a rectal temperature) where it will be held in this position for five seconds. The 
rectal swabs or stool samples for both clinical sites will be tested, stored, and shipped to 
the Infectious Disease Research Laboratory (IDRL) at Children’s Hospital of Pittsburgh 
(PITT). These samples will be analyzed at a central lab to determine the presence of 
antimicrobial resistance in isolates of E. coli and K. pneumonia. 
At CHOP, study staff will send collected specimens directly to the IDRL at PITT via UPS. 
Study staff will be trained according to the International Air Transport Association (IATA) 
requirements. The specimen and the UPS tracking number will be logged in the 
database before shipping to the IDRL.  
Inoculated swabs will be placed in Cary Blair transport media. All specimens will be 
refrigerated immediately upon collection and be shipped the same day via overnight mail 
to the PITT IDRL. If specimens cannot be immediately shipped, they will be placed in a 
2-8°C refrigerator and shipped on the next business day. At CHOP, stool specimens will 
initially be stored at the specimen collection, processing and point of care core lab of the 
CTRC at CHOP before they are sent to the PITT IDRL. Study staff will send the 
specimens collected at the outpatient clinics or at subject’s homes (away from the CHOP 
main campus) directly to the IDRL at PITT. Specimens collected from subjects at 
Children’s Hospital of Pittsburgh will be hand-delivered to the IDRL by study personnel. 
 
For each subject at CHOP who agrees to participate in the Microbiome pilot study, an 
additional perirectal swab and anal swab will be collected. The anal swab will be 
collected by brushing the swab back and forth five times against the skin just outside of 
the rectum. For subjects in diapers, a third swab will be collected from the stool in the 
diaper if one is available.  
9.2.3.2 Specimen Shipment 
Inoculated stool swabs will be placed in Cary Blair transport media and will be mailed via 
UPS to the PITT IDRL of the University of Pittsburgh Medical Center, which serves as 
the central microbiology core laboratory for this project. 
 
Swabs collected for the Microbiome sub-study will be shipped the same day via 
overnight mail to the Knights Lab at the University of Minnesota. If specimens cannot be 
immediately shipped, they will be placed in a -20°C freezer and shipped on the next 
business day.  
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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10 
ASSESSMENT OF SAFETY 
10.1 Specification of Safety Parameters 
Safety will be evaluated by the collection and analysis of data on serious adverse events 
(SAEs), clinical laboratory tests, pain assessments, and concomitant medications. The 
investigator is responsible for documenting all SAEs that are observed or reported 
throughout the study regardless of their relationship to the study products or procedures.  
The study products used in this protocol are established generic products labeled for use 
in the study population for treatment in the indication, UTI. TMP-SMX cefixime, and 
cephalexin have been used to treat UTIs in children for decades, have established 
safety records for pediatric use, and have well described side effect profiles. These are 
the four most commonly prescribed antibiotics at CHOP and PITT for the treatment of 
UTIs in children.   
The subjects will be followed from the Enrollment Visit through the Day 38 – 44 follow-up 
phone call (four weeks after completing study product therapy). Subjects on the 
continued antibiotic treatment arm may have a higher likelihood of developing resistant 
bacteria than subjects on the placebo arm; however, their risk should be no greater than 
what occurs in standard clinical practice.  
For the purposes of this study, adverse events will be collected from the initiation of the 
study product (Day 6) through the Day 38 - 44 Follow-up Phone Call (four weeks after 
finishing the study product).  
Study subjects will be educated at the time of enrollment in the study about the signs 
and symptoms of a relapse UTI and the benefits of prompt and adequate treatment as 
well as the possible side effects of the study product. The study nurses, nurse 
practitioners and investigators at each site will be available on a 24-hour basis, through 
a study-dedicated cellular phone. Study subjects will be asked to contact study staff with 
any symptoms or complaints potentially related to the intervention. In addition, at each 
study visit, the Study Nurse/Nurse Practitioner/Physician will perform assessments of the 
subjects. At each of these contacts and visits, parent(s) or guardian(s) will be asked to 
report any inter-current illnesses or symptoms. If a study RN receives a report of a UTI 
symptom at any study visit, he/she will inform the parent/guardian that the child should 
be seen by a clinician licensed to diagnose and treat the UTI. The RN will document the 
symptom on the appropriate case report form. If the report occurs at the enrollment visit, 
the child will be referred back to the PCP that treated that child initially. If the symptom 
report occurs after the child has started SCOUT medication, the RN will contact a study 
physician to arrange follow-up visit. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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Monitoring of the data is an essential part of the research plan for subject safety. 
Reporting adverse events and unanticipated problems is an essential part of the 
research plan for safety and compliance. 
 
10.2 Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
At each contact with the subject (at the two follow-up study visits and the day 38 – 44 follow-up 
phone call), information regarding adverse events will be elicited through appropriate UTI 
symptom questioning and pain assessment (at the study visits) for any suprapubic, abdominal, 
or flank pain or tenderness) and will be immediately recorded on a source document. Source 
documents will include: progress notes, laboratory reports, consult notes, phone call 
summaries, medication diaries, survey tools and data collection tools. Source documents will be 
reviewed in a timely manner by the research team. All adverse events that are identified will be 
recorded on an appropriate case report form (CRF). The start date, the stop date, the severity of 
each event, and the Investigator’s judgment of the AEs relationship to the study product and/or 
study procedure will also be recorded on the subject’s CRF. 
The Investigators are responsible for the accurate documentation, investigation and follow-up of 
all possible study-related adverse events.  Clinical site staff will be given appropriate training on 
AE system for grading the severity of events during the protocol training session. 
All SAEs will be documented on an SAE Reporting form. Sites will fax all AERs to CHOP ((267)-
426-0380) and PITT ((412)-692-5807) for immediate review and action if necessary. All AERs 
and Safety Reports will be tracked in the computerized AE Tracking System, and data on every 
AER will be entered into the AE database. 
Clinical site monitors will review medical records and source documentation during on-site 
monitoring visits to determine if all AEs were appropriately identified, reported and managed. 
Monitoring of the data is an essential part of the research plan for subject safety. Reporting AEs 
and unanticipated problems is an essential part of the research plan for safety and compliance. 
 
10.2.1 Adverse Events 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product regardless of its causal relationship to the study 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of medicinal 
(investigational) product.  The occurrence of an AE may come to the attention of study 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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personnel during study visits and interviews of a study recipient presenting for medical care, or 
upon review by a study monitor.  
All AEs including local and systemic reactions not meeting the criteria for “serious adverse 
events” will be captured on the appropriate CRF.  Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis, which would 
include MD, PA, Nurse Practitioner, DO, or DDS), and time of resolution/stabilization of the 
event.  All AEs occurring while on study must be documented appropriately regardless of 
relationship.  All AEs will be followed to adequate resolution.  
Any medical condition that is present at the time that the patient is screened should be 
considered as baseline and not reported as an AE.  However, if it deteriorates at any time 
during the study, it should be recorded as an AE.  
All AEs must be graded for severity and relationship to study product.  
FDA defines an AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Severity of Event:  All AEs will be assessed by the clinician using a protocol defined grading 
system.  For events not included in the protocol defined grading system, then the following 
guidelines will be used to quantify intensity.  
Mild:  events require minimal or no treatment and do not interfere with the patient’s daily 
activities. 
Moderate:  events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
Severe:  events interrupt a patient’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually incapacitating. 
Life threatening:  any adverse drug experience that places the patient or subject, in the view of 
the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that had it occurred in a more severe form, might have caused death. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of intensity to be performed.  We will document the duration of each 
episode characterized as intermittent. 
Relationship to Study Products, Study Procedures and Initial UTI:  The clinician’s 
assessment of an AE's relationship to the study product, study procedures and initial UTI is part 
of the documentation process, but it is not a factor in determining what is or is not reported in 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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the study.  If there is any doubt as to whether a clinical observation is an AE, the event will be 
reported.  All AEs will have their relationship to study product assessed using the terms:  related 
or not related.  In a clinical trial, the study product must always be suspect.  To help assess, the 
following guidelines will be used. 
• 
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
10.2.2 Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• 
Death, 
• 
A life-threatening adverse event*,  
• 
Inpatient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
• 
A congenital anomaly/birth defect.   
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
* Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death.  It does not include an adverse event, had it occurred in a more 
severe form, might have caused death. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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All SAEs will be: 
• 
Recorded on the appropriate SAE CRF 
• 
Followed through resolution by a study clinician 
• 
Reviewed and evaluated by a study clinician 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major event 
of its type.  A severe AE does not necessarily need to be considered serious.  For example, 
nausea that persists for several hours may be considered severe nausea, but would not be an 
SAE.  On the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke, but would be an SAE. 
10.2.3 Procedures to be Followed in the Event of Abnormal Laboratory 
Test Values or Abnormal Clinical Findings 
No laboratory tests are planned for this study other than urine and stool analysis.  Abnormal 
clinical findings and laboratory test values (if available) will be documented in the source 
document.  A study clinician will review all study lab results to determine clinical significance. 
Those meeting criteria of SAE will be reported as per Section 10.4. 
 
10.3 Reporting Procedures 
10.3.1 Adverse Events 
AEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic.  All AEs collected during the study will 
be documented on the appropriate CRF.  CHOP and PITT are responsible for reporting adverse 
events to their local IRB in accordance with the local IRB requirements. The PI or a co-
investigator at each site will determine the proper response per the research protocol—i.e.: 
changing therapy, initiating new therapy, or having the subject discontinue study product (of 
days six - ten).  
10.3.2 Serious Adverse Events 
If in the opinion of a study physician investigator (PI or co-investigator) the event meets the 
criteria of a SAE the following procedures will occur. 
 
 All SAEs will be: 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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• 
Recorded on the DMID SAE reporting form and the SAE CRF by study staff. 
• 
Reviewed by PI or co-investigator, who will assess the event’s relationship to 
study product or procedures. All SAEs will be assessed for relationship to the 
study research procedures.  A causal relationship means that the study 
participation caused (or is reasonably likely to have caused) the event.  This 
usually implies an association in time between a study procedure and the event. 
• 
Followed by PI or co-investigator until satisfactory resolution or until the PI or co-
investigator or deems the event to be chronic or the subject to be stable. 
• 
If an SAE has not resolved at the time of the initial report, a follow-up SAE 
reporting form must be submitted and a follow-up SAE CRF must be completed.  
SAEs will be followed until resolution or stabilization if the event is expected to 
remain chronic. 
 
Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance 
Group, at the following address:  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS)  
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20814, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
All SAEs regardless of relationship will be recorded on the SAE form and sent by fax within 24 
hours of site awareness of the event.  Other supporting documentation of the event may be 
requested by the DMID Pharmacovigilance Group and should be provided as soon as possible. 
This may include all relevant new or reassessed information (e.g. concomitant medication, 
medical history).  Follow-up information will be submitted to the IRB and DMID 
Pharmacovigilance Group who will provide this to the DMID medical monitor and clinical 
program manager. All SAEs will be followed until either resolved or stable.  
The DMID medical monitor and clinical protocol manager will be notified of the SAE by the 
DMID Pharmacovigilance Group. The DMID medical monitor will review and assess the SAE for 
regulatory reporting and potential impact on study subject safety and protocol conduct.  
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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At any time after completion of the study, if the investigator becomes aware of an SAE that is 
suspected to be related to study product, the investigator will report the event to the DMID 
Pharmacovigilance Group.  
 
Serious adverse events will be reported to the independent Data Safety Monitoring Board 
(DSMB) according to the guidelines and schedule established by that group in the charter. All 
adverse events and safety data will be reported to the DSMB through regularly scheduled 
reports. 
 
The Principal Investigator will promptly notify the IRB of all study on-site SAEs and other 
unanticipated problems related to research using the CHOP Internal SAE reporting form and in 
accordance with the following timeline. External SAEs that are unexpected and related to the 
study intervention should be reported as received using the External SAE form (if applicable).  
 
Table 7: IRB Adverse Event Notification 
Type of Internal Adverse Event 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening 
24 hours 
Within five calendar days 
Internal (on-site) SAEs 
All other SAEs 
72 hours 
Within five calendar days 
Unanticipated Problems Related to 
Research 
72 hours 
Within five calendar days 
All other Events 
N/A 
As per local IRB requirement  
 
10.3.3 Regulatory Reporting for Studies Conducted Under DMID-
Sponsored IND 
Following notification from the investigator, DMID, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  DMID will report an adverse event as a 
suspected adverse reaction only if there is evidence to suggest a causal relationship between 
the drug and the adverse event.  DMID will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, but in no case later than 15 calendar days after the sponsor determines that 
the information qualifies for reporting as specified in 21 CFR Part 312.32. DMID will also notify 
FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible 
but in no case later than 7 calendar days after the sponsor’s initial receipt of the information. 
Relevant follow up information to an IND safety report will be submitted as soon as the 
information is available.  Upon request from FDA, DMID will submit to FDA any additional data 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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or information that the agency deems necessary, as soon as possible, but in no case later than 
15 calendar days after receiving the request. 
All serious events designated as “not related” to study product(s), will be reported to the FDA at 
least annually in a summary format. 
10.4 Type and Duration of Follow-up of Subjects after Adverse 
Events 
After the initial SAE report, the investigator will follow each subject and provide further 
information to the DMID medical monitor on the subject’s condition. All AEs documented 
at a previous visit/contact and are designated as ongoing, will be reviewed at 
subsequent visits/contacts. All AEs will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up. 
Once resolved, the appropriate AE source document and CRF pages will be updated. 
The investigator will ensure that follow-up includes any supplemental investigations as 
may be indicated to elucidate the nature and/or causality of the AE. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
 
All AEs reported in this study will be followed until resolution or until the investigator and 
the clinical monitor are in agreement that the AE has stabilized and no additional follow-
up is required. This requirement indicates that follow-up may be required for some 
events after the participant discontinues participation from the study. These events will 
be reported to the IRB annually, as well as the DSMB, according to the frequency 
defined by the DSMB Charter.  
10.5 Halting Rules 
 
Because of the masked nature of the study design, the treatment failure for UTI cannot 
be monitored in the short-course arm alone. However, we will monitor the failure rate 
separately in BOTH arms for the first 100 subjects in each arm. To ensure patient safety 
the following early halting rule will be applied separately to each study arm:  
 
Stop accrual/suspend if at any stage:  
3 among the first 16 patients experience a treatment failure 
5 among the first 23 patients experience a treatment failure 
6 among the first 29 patients experience a treatment failure 
7 among the first 36 patients experience a treatment failure 
8 among the first 43 patients experience a treatment failure 
9 among the first 49 patients experience a treatment failure 
10 among the first 56 patients experience a treatment failure 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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11 among the first 63 patients experience a treatment failure 
12 among the first 69 patients experience a treatment failure 
13 among the first 76 patients experience a treatment failure 
14 among the first 83 patients experience a treatment failure 
15 among the first 89 patients experience a treatment failure 
16 among the first 96 patients experience a treatment failure 
17 among the first 100 patients experience a treatment failure 
 
The halting probabilities (based on sequential Bernoulli outcomes) of the halting rule 
above are displayed in Table 8 below. 
 
 
Table 8: Probability of stopping in terms of true treatment failure rate for UTI and 
number of patients enrolled on the study 
 
 
  Treatment failure rate 
No. of 
Subjects 
5% 
15% 
20% 
15 
0.04 
0.40 
0.60 
20 
0.04 
0.44 
0.65 
25 
0.04 
0.46 
0.69 
30 
0.04 
0.48 
0.72 
35 
0.04 
0.51 
0.75 
40 
0.04 
0.52 
0.78 
50 
0.04 
0.56 
0.82 
60 
0.04 
0.59 
0.86 
70 
0.04 
0.61 
0.88 
80 
0.04 
0.63 
0.90 
90 
0.04 
0.65 
0.92 
100 
0.04 
0.67 
0.93 
 
Thus, if the true treatment failure rate is 5%, then the probability of terminating accrual at 
the 25th patient is 4%. Note that this probability converges to 4% and will be expected to 
remain at this value for the rest of the study. In contrast, if the true treatment failure rate 
is 15%, the probability of stopping accrual at the 25th patient is 46%.  
In addition, any SAE considered related to the study procedures or products will be 
reported to the DMID Medical Monitor and DSMB members and a safety evaluation will 
be conducted by electronic review. Upon reviewing the event members of DSMB or/and 
DMID MM may request an ad hoc meeting to further discuss it. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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The ad hoc meeting of the DSMB will be organized to determine if the study may 
proceed without changes, should be revised, or even terminated.  The PI and/or DMID 
may request ad hoc meetings of the DSMB  
The IRB, NIAID, and the FDA as part of their duties to ensure that research subjects are 
protected; may discontinue the study at any time. Subsequent review of serious, 
unexpected and related adverse events by the DMID Medical Monitor, DSMB, the ethics 
review committee or IRB, NIAID, the FDA, and other regulatory authorities may also 
result in suspension of further trial interventions/administration of study agent at a site. 
The FDA, other regulatory authorities, and NIAID retain the authority to suspend 
additional enrollment and study product administration for the entire study as applicable. 
If rates of study product-related SAEs are unexpectedly high, the DMID medical monitor 
will promptly conduct a safety review involving the DSMB to determine if suspension of 
enrollment is warranted.  
10.6 Safety Oversight  
 
Safety oversight will be under the direction of a DSMB which will consist of at least 3 
voting members including a biostatistician experienced in statistical methods for clinical 
trials and a clinician with relevant expertise.  The DMSB will operate under the rules of a 
DMID-approved charter written at the organizational meeting of the DSMB.  At this time, 
each data element that the DSMB needs to assess will be clearly defined.  During the 
course of the study, the DSMB will meet at least annually to assess safety and efficacy 
data on each arm of the study.  The DSMB will review aggregate safety data for 
increased rate of occurrence of serious suspected adverse reactions. If halting rules are 
initiated, more frequent meetings may be held.  The DSMB will advise DMID of its 
findings. 
 
Unmasking intentional or unintentional is strongly discouraged and must be approved by 
DMID.  However, if such event(s) occur, the Principal Investigator and co-Investigators 
will notify the DMID immediately, so that the DSMB can be made aware and assess the 
potential impact of the unmasking on the overall integrity of the study.  
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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11 CLINICAL MONITORING 
11.1 Site Monitoring Plan 
Subcontractor, Westat will provide monitoring and safety oversight for the SCOUT Study 
for all aspects of clinical site and laboratory monitoring, pharmacy auditing, quality 
control and adverse event reporting.  Their responsibilities in this capacity include 
development of a site monitoring plan; monitoring of sites for protocol adherence, 
competence of staff, observance of quality assurance procedures; proper storage and 
security of study product, maintenance of records and subject eligibility; inspection of 
IRB approval documents; review of subject records for protocol adherence, accuracy, 
completeness and source document verification; meetings with study staff to review 
findings, problems, deficiencies and possible solutions; and reporting through CHOP to 
the DMID Project Officer to summarize key findings, deficiencies and corrective actions. 
Westat site monitors will visit the CHOP and PITT research sites to review a selected 
proportion of the individual subject records, including consent forms, CRFs and 
supporting source documentation to ensure protection of study subjects, compliance 
with the protocol, and accuracy and completeness of records.  Eligibility will be 
confirmed for 100% of subjects; and full chart review will be performed for five percent of 
subjects, unless performance issues indicate that more extensive review is advisable. 
Regulatory files will also be inspected to ensure that regulatory requirements are being 
followed. The clinical monitoring plan will be reviewed and approved by the DMID. In 
addition, DMID will be sent all monitoring reports and that DMID retains the right to 
assess the quality of monitoring at any time during the study. 
Westat site monitors will also visit the CHOP and PITT study product area to review the 
overall study product management system, including receipt, storage, disposition and 
accountability of study products.   
The site investigators and study teams will make study documents (e.g. consent forms, 
case report forms) and pertinent hospital and clinical records available for inspection by 
the local IRB, the site monitors, the FDA, NIAID, the Office of Human Research 
Protection (OHRP), or the sponsor’s designee for confirmation of the study data. Per 
DMID Source Documentation Standards for DMID clinical studies, v2, March 16, 2004 - 
if any original records/source documents cannot be made available to monitors for 
verification of data collected, a “Certified Copy” of the records can be made and kept as 
part of a separate research record. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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12 
STATISTICAL CONSIDERATIONS 
12.1 Study Objectives 
 
Primary Objective: 
 
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 TOC (visit Day 11-14) as subjects who 
continue to take antibiotics for an additional 5 days  (standard course therapy).  
 
Secondary Objectives:    
 
To determine if short-course therapy compared to standard course therapy results in 
similar numbers of children experiencing a recurrent infection (relapse and reinfection). 
 
To determine if short-course therapy compared to standard course therapy results in 
similar numbers of children with asymptomatic bacteriuria.   
 
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 pneumoniae (K. pneumoniae).  
 
To determine if short-course therapy compared to standard course therapy results in  
similar numbers of children with clinical symptoms that may be related to a UTI. 
 
To determine if short-course therapy compared to standard course therapy results in 
similar numbers of subjects with positive urine cultures prior to or at the TOC visit.  
 
Sub-Study Objectives: 
 
To determine if E. coli and K. pneumonia recovered from 2 or 3 stool cultures are more 
likely to be members of disease-associated subgroups within their respective species (E. 
coli phylogroups B2 and D, K. pneumoniae clusterKpI) 
 
To determine if treatment-susceptible strains recovered from cultures during treatment 
(culture #1 for 5-day arm; cultures #1 or #2, 10-day arm) are more likely to be members 
of disease-associated subgroups;  


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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To determine if treatment-resistant strains of either species are more likely than 
treatment susceptible strains to be recovered from cultures during treatment 
 
To determine the overall prevalence of colonization with carbapenem-resistant 
Enterobacteriaceae (overall and for specific pathogens) in ambulatory children after 
completion of treatment for UTI 
 
To compare the overall biodiversity of the gut microbial community, as measured by 
culture-independent marker gene sequencing at each follow-up visit following short-
course and standard-course antibiotic exposure. 
To compare the overall fraction of gut microbiome community represented by 
gammaproteobacteria measured by culture-independent marker gene sequencing at 
each follow-up visit following short-course and standard-course antibiotic exposure. 
To compare the average ecological similarity between microbial communities within and 
between treatment groups at each follow-up following short-course and standard-course 
antibiotic exposure. 
 
To describe the breadth of bacteria present in the stool of children receiving therapy for 
a urinary tract infection. These data will allow for comparison of aerobic bacteria stool 
composition in these children and present an opportunity to contrast them to similar data 
available from other pediatric patient populations.    
12.2 Sample Size Considerations 
The primary aim of this study is to determine if halting antimicrobial therapy in subjects 
that show clinical improvement 5 days after starting antibiotic therapy (short course 
therapy) is as effective as continued therapy through day 10 (standard course) as 
determined by treatment failure rate (symptomatic UTI) through TOC visit Day 11-14 (6-
9 days after starting per protocol therapy). 
.  
The treatment failure rate under the standard of care, R0, is expected to be 5%. This 
estimate is based on data from previously published studies [43, 47]. The power and 
sample size calculations are based on the assumption that treatment failure  under the 
short-course therapy, RSC, will range from 5% to 9%.  
In the non-inferiority test, on which power and sample size are based, the null 
hypothesis that short-course therapy is inferior to standard-of-care therapy is tested 
against the alternative that short-course therapy is non-inferior. That is, H0: RSC, > R0, + 
δ is tested against Ha: RSC,  R0, + δ, where δ is the “interval of equivalence,” the range 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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in which the treatment failure rates of the two therapies would be considered clinically 
equivalent. We believe that an interval of equivalence of 5% would be clinically 
acceptable; a success rate of 95% for the standard-of-care therapy group when 
compared to 90% for the short-course therapy group. For all power and sample size 
calculations, the significance level (chance of incorrectly failing to reject the null 
hypothesis) is α = 0.05. 
12.3 Planned Interim Analyses  
An interim analysis for the primary outcome measure will be performed once half the 
subjects have enrolled (to get 336 subjects who are evaluable for the primary endpoint). 
This analysis will test the null hypothesis that the treatment failure rate under short 
course therapy is equal to (or less than) that of standard therapy against the alternative 
hypothesis that the failure rate under short-course therapy is greater than using 
standard-of-care therapy. This test will be one-sided with α = 0.05. The endpoint for this 
analysis will be the treatment failure rate. The statistical test will be a one-sided test of 
the hypothesis of equal failure rates between the two study arms. 
As part of the interim data analyses, conditional power estimates may be made.  The 
conditional power analysis is a re-assessment of the power given the results of the study 
to date. Large, early differences imply high conditional power; but small differences in 
the early part of a study may suggest lower power than initially expected.  
The methods for the planned statistical interim analysis will be described and justified in 
the Statistical Analysis Plan (SAP), including the timing of the interim analyses (i.e., 
when half of the subjects have completed the study), the scope of the interim analysis 
including a description of which endpoints will be analyzed (i.e., efficacy analysis of the 
primary endpoint), and the methods or statistical tests that will be used in the analyses. 
Note that since the interim analysis is for superiority of standard therapy and the final 
efficacy analysis is for non-inferiority of short-course therapy, there is no impact of the 
interim analysis on the Type I error of the final efficacy analysis and thus no adjustments 
to the significance level are required.  The SAP will be written prior to the interim 
analysis.  
12.4 Final Analysis Plan 
General Design: The data analysis will consist of several parts. First, descriptive and 
baseline statistics will be generated for outcome measures for the purpose of describing 
the study population and comparing the two study arms at baseline. Second, the primary 
and secondary analyses will be conducted. Finally, primary and secondary outcome 
measures will be compared between various subgroups of the study participants to 
assess potential interactions with treatment effects.  Details will be provided in the 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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statistical analysis plan (SAP) which will be finalized prior to the interim analysis.  A 
general description of the planned approach is provided below. 
 
Study Endpoints:  
 
The primary outcome measure is: 
 
Comparison of efficacy, based on symptomatic UTI as assessed at the TOC visit (Day 
11-14), between short-course and standard-course of antibiotics. 
 
The secondary outcome measures are: 
 
Comparison of number of subjects that have a recurrent infection (includes a relapse 
UTI or a reinfection) at any time after the TOC visit (Day 11-14), following a short-course 
versus standard-course of antibiotics.   
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 as assessed through Day 24-30, following short-course (5-day) 
versus standard course (10-day) of antibiotics. 
Comparison of the number of subjects with asymptomatic bacteriuria following short-
course (5-day) versus standard course (10-day) of antibiotics. 
Comparison of the number of subjects with clinical symptoms that may be related to a 
UTI following short-course (5-day) versus standard course (10-day) of antibiotics. 
Comparison of the number of subjects with positive urine culture prior to or at the TOC 
visit following short-course (5-day) versus standard course (10-day) of antibiotics. 
 
The sub-study outcome measures are:  
 
Seattle R21 
Presence of E. coli, presence of K. pneumoniae  
Sub-types of E. coli (0=phylogroups A or B1, 1=phylogroups B2 or D), sub-types of K.         
pneumoniae  
Presence of treatment-susceptible E. coli, presence of treatment-susceptible K. 
pneumoniae  
Presence of treatment-resistant E. coli, presence of treatment-resistant K. pneumoniae 
Carbapenem-resistant Enterobacteriaceae 
Presence of carbapenem-resistant Enterobacteriaceae (overall and for specific 
pathogens).  


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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Microbiome pilot study 
Comparison of the overall biodiversity of the gut microbial community, as measured by 
culture-independent marker gene sequencing at each follow-up visit following short-
course and standard-course antibiotic exposure. 
Comparison of overall fraction of gut microbiome community represented by 
gammaproteobacteria measured by culture-independent marker gene sequencing at 
each follow-up visit following short-course and standard-course antibiotic exposure. 
Comparison of average ecological similarity between microbial communities within and 
between treatment groups at each follow-up following short-course and standard-course 
antibiotic exposure. 
 
Spectrum of Stool Bacteria 
Description of the bacteria present on the aerobic stool cultures obtained at each the 
three study time points. 
 
Descriptive Analysis: Standard descriptive statistics will be used to describe subjects’ 
baseline characteristics at the time of enrollment, as well as study outcome measures 
overall and within each treatment group. Summary statistics such as means, standard 
deviations, medians, and ranges will be produced for continuous variables. Frequency 
counts and percentage will be generated for describing variables that are dichotomous 
or polytomous in nature.  The balance of baseline measures (i.e., at the time of 
enrollment) between short-course therapy group and standard-of-care therapy group will 
be compared using two-sample tests, including t-tests, the Mann-Whitney test, chi-
square tests, and so forth, as appropriate. 
 
Primary Analysis / Efficacy Analysis: The primary analysis will follow Intent-to-Treat (ITT) 
principles, with subjects analyzed according to randomized treatment assignment. In 
addition, a “per-protocol” analysis will be performed; the per-protocol analysis would 
include only subjects who were adherent to their assigned study regimen and completed 
80% or more of the prescribed dose. All subjects taking at least one dose of study 
drug(s) who have been evaluated for treatment success at TOC visit or have failed 
treatment prior to TOC will be included in the ITT analysis (see the table below). The 
primary analysis will be a non-inferiority test comparing the number of symptomatic UTIs 
at the TOC visit between two treatment arms along with the 5% equivalence interval. 
The confidence interval of the difference in symptomatic UTI rates between the short-
course and standard-of-care therapies will be calculated to evaluate whether this 
difference is less than or equal to the equivalence interval.  This will be a one-sided test 
with α = 0.05. Subjects with asymptomatic bacteriuria or who are asymptomatic with a 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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positive culture including pyuria will NOT be considered treatment failures for the primary 
outcome measure.   
 
Table 9: SCOUT Study product Dosage Adherence  
Antibiotic Drug 
Antibiotic Dosage 
80% of Expected Doses 
Trimethoprim-
Sulfamethoxazole 
 (TMP-SMX) 
8 mg/kg/day of Trimethoprim 
in 2 divided doses,  
Max 160mg BID Trimethoprim 
Eight doses 
 
Amoxicillin-Clavulanate* 
45 mg/kg/day in 2 divided 
doses, 
Max 875 mg Q12H 
Eight doses 
Cefixime 
8 mg/kg/day in 1 dose, 
Max 400 mg 
Four doses 
Cephalexin 
50mg/kg/day in 3 divided 
doses 
Twelve Doses 
*Amoxicillin-clavulanate is no longer included as a study antibiotic, but subjects randomized to this 
treatment prior to its removal must have taken at least eight doses to be included in the per-protocol 
analysis. 
 
 
Secondary Analysis:  
The secondary outcome measures of this trial are provided above.  A difference 
between the two arms with regards to asymptomatic bacteriuria, presence of clinical 
symptoms, and negative urine culture is not expected. No difference will mean that 
shorter courses of antibiotics for treatment are not inferior to long courses in eradicating 
bacteria from the urinary tract as well as impacting clinical symptoms. This analysis will 
be a conventional test for efficacy and will consist of a straightforward two-sample test 
for a difference between proportions, using a two-sided chi-square test at significance 
level of .05.  
Sub-study Analysis:  
Seattle Children’s Hospital R21 
As previously noted, patient stool samples will be collected on 3 occasions. For primary 
analysis, cross-sectional analysis will be performed, i.e. looking at samples from one 
occasion at a time. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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For each occasion, the following proportions will be summarized:  
1) Among all patients, proportion of patients with E. coli detected, proportion of patients 
with K. pneumoniae detected, and same proportions within each treatment arm. 
2) Among patients with E. coli detected, proportions of sub-type 0 or sub-type 1; among 
patients with K.pneumoniae detected, proportions of the two sub-types, and same 
proportions within each treatment arm. 
3) Among patients with E. coli detected, proportions of treatment-susceptible E. coli; 
among patients with K. pneumoniae detected, proportion of treatment-susceptible K. 
pneumoniae; and same proportions for different treatment arms. 
4) Among patients with E. coli detected AND treatment-susceptible, proportions of sub-
type 1; among patients with K. pneumoniae detected AND treatment-susceptible, 
proportions of sub-type 1; and same proportions for different treatment arms 
5) Among patients with E. coli detected proportion of treatment-resistant E. coli; among 
patients with K.pneumoniae detected, proportion of treatment-resistant K. pneumoniae; 
and same proportions within different treatment arms. 
 
After obtaining the proportions listed in (2) above, a binomial test will be used to 
determine whether the proportion of E. coli sub-type 1(phylogroups B2 and D) is 
significantly larger than 50%. A chi- square test will also be used to test the differences 
in proportions of sub-type 1 across treatment arms. In addition, a multivariable logistic 
regression on presence of sub-type 1 strains will be conducted.  The same approach will 
be used for K. pneumoniae sub-type 1. 
 
For culture #1 (5-day treatment arm), or culture #1 or #2 (10-day treatment arm), the 
proportions of sub-type 1 will be tested using a binomial test, then a  logistic regression 
will be used to examine the association between presence of subtype 1 strains and 
treatment arms. 
 
A chi-square test will be used to examine the difference in proportions estimated in (3) 
and (5) above. Logistic regression models will also be used for analysis.  
 
Microbiome pilot study 
We will preprocess all marker-gene microbiome sequencing data using the Quantitative 
Insights Into Microbial Ecology (QIIME) software package [PMID: 20383131]. This will 
include performing sequence quality filtering and demultiplexing of reads to separate 
sequences by sample. For taxonomic marker gene and RNA-Seq sequences, we will 
stitch overlapping paired-end reads together after demultiplexing using PANDAseq 
[PMID: 22333067]. We will then map marker gene reads to 97% operational taxonomic 
units (OTUs) using the Greengenes [PMID: 22134646] reference database and the 
USEARCH [PMID: 20709691] reference mapping software wrapped by QIIME. We will 
measure within-sample biodiversity (alpha diversity) based on these OTUs using whole-
tree phylogenetic diversity56 and the Greengenes reference phylogeny. To quantify 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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differences in microbial carriage and composition between and within subjects over time, 
we will calculate the UniFrac distance [PMID: 20827291] between all pairs of samples. 
UniFrac is a measure of the fraction of the evolutionary tree relating all observed taxa 
that is not overlapping between two samples. To visualize these within- and between-
subject differences (beta diversity) and to obtain principal components for subsequent 
statistical testing, we will perform dimensionality reduction using principal coordinates 
analysis. To enable tests for shifts in the relative abundance of both broad and specific 
bacterial taxa with respect to the host factors mentioned above, we will collapse the 
reference-based OTUs according to taxonomy at the genus and phylum levels using 
QIIME. This will produce culture-independent fractional observation counts of bacterial 
taxa in all samples.  
We will test for overall differences in microbiome composition between short-course and 
standard-course antibiotics. To test for associations between individual bacterial taxa 
and these groups, we will perform non-parametric Mann-Whitney U tests. We will 
perform a similar test for association of microbiome biodiversity with treatment and 
between-sample diversity as well as gammaproteobacteria relative abundance.. In all 
cases the significance of association will be determined after correcting for multiple 
comparisons using false discovery rate. 
 
Subpopulation Analyses: Treatment effects for the primary and secondary outcome 
measures  will be estimated as differences between proportions and compared for 
subpopulations defined by age groups, febrile or non-febrile UTI (at original UTI 
diagnosis), and type of originally prescribed antibiotic. First, proportions will be tabulated 
as two-sample comparisons and chi-square tests for treatment differences in the 
outcomes within subgroups will be calculated.  Factors where significant differences are 
observed will be further assessed using logistic regression analysis, assuming that the 
logistic model fits the data.  Goodness of fit test will be reported for model checking. 
Treatment-by-subpopulation interactions will be tested using likelihood ratio tests. The 
power of these comparisons is expected to be low for both primary and secondary 
endpoints. The study is only likely to detect marked differences in treatment effects in 
these subpopulations.  
Safety Analysis: Safety in this study is related to efficacy. Safety will be evaluated by the 
collection and analysis of data on SAEs, clinical laboratory tests, pain assessments, and 
concomitant medications. The investigator is responsible for reporting all SAEs that are 
observed or reported up, regardless of their relationship to study product. Serious 
adverse events and abnormal laboratory (if available) results will be compared by 
treatment arm, with statistical tests for differences in proportion of subjects with serious 
adverse events between study arms.  


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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Missing Data: Several procedures will be used to conduct data analysis when data for 
either outcomes or covariates are missing.  The first step will be to assess the extent 
and pattern of missing data.  If data are missing for only a few cases, then data analysis 
will be conducted only on study participants with complete data.  However, when such a 
strategy would result in loss of data from a substantial proportion of participants or would 
lead to biased or inaccurate results, then some form of imputation will be performed.  
The form of imputation used will depend on the nature of the data that are missing.  
Attrition and Loss to Follow-up: It is expected that loss to follow-up will be minimal in this 
study. Because the study is of short duration, we are hopeful that we will able to follow 
virtually all subjects to study completion. However, some study participants may 
withdraw consent or may not return for the follow-up visits to determine the primary 
endpoint. Other participants may not have the endpoint determined due to problems with 
specimens or laboratory processing. We anticipate that these factors may reduce the 
sample size by as much as 10%. Thus the sample was increased by approximately 11% 
to offset this sample size reduction. Note that study participants who disrupt or 
discontinue study treatment will continue with follow-up and have the study endpoints 
assessed, and will be included in the ITT analysis.  


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Subject information will only be entered into the database once the informed consent form / 
assent form (if applicable) has been signed and the child is formally enrolled. Preliminarily 
screened subject information will be kept in an on-site password protected locked 
database.  
 
Study data will be collected on case report forms (CRF) designed for the study.  The 
Principal Investigator is responsible for assuring that the data collected is complete, 
accurate, and recorded in a timely manner. Source documentation (the point of initial 
recording of a piece of data) should support the data collected on the case report form, and 
in the case of CRFs, they will be signed and dated by the person recording and/or 
reviewing the data.  Source documents include all recordings of observations or notations 
of clinical activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical trial. Data for CRFs will be collected during subject visits, 
phone calls with subjects and health care providers, medication diaries and abstracted from 
the medical record. The CRF forms will also include the lab results from the subject’s initial 
urine analysis, the test of cure urine sample, and their three stool samples collected at each 
of the three study visits. 
 
If any original records/source documents cannot be made available to monitor for 
verification of data collected, a “Certified Copy” of the records can be made and kept as 
part of a separate research record. 
 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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14 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a DMID-approved Quality Management Plan approval, the CHOP and PITT 
sites will be responsible for conducting routine quality assurance (QA) and quality control 
(QC) activities to internally monitor study progress and protocol compliance.  The 
Principal Investigator will provide direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, 
and inspection by local and regulatory authorities. The Principal Investigator will ensure 
all study personnel are appropriately trained and applicable documentations are 
maintained on site.  
 
Westat, the SCOUT site monitor subcontract, will verify that the clinical trial is conducted 
and data are generated, documented (recorded), and reported in compliance with the 
protocol, Good Clinical Practice, and the applicable regulatory requirements.  Clinical 
monitoring reports will be submitted to CHOP and PITT for their review. A summary of 
the site monitoring reports will be included in the monthly safety reports that are 
submitted to DMID.  
 
The CHOP-BDMC will implement quality control procedures beginning with the data 
entry system and generate data quality control checks that will be run on the database. 
Any missing data or data anomalies will be communicated to the site(s) for clarification 
and resolution. 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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15 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
15.1 Ethical Standard 
The investigators will ensure that this study is conducted in full conformity with principles 
of the Belmont Report:  Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the National Commission for the Protection of Human Subjects 
of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR 46, 21 
CFR 50 and 56, and ICH E6; 62 Federal Regulations 25691 (1997), if applicable.  The 
investigator’s Institution will hold a current Federal Wide Assurance (FWA) issued by 
OHRP for federally funded research. 
15.2 Institutional Review Board 
A copy of the protocol, informed consent forms, other information to be completed by 
participants, such as survey instruments or questionnaires, and any recruitment 
materials, symptom and inclusion/exclusion criteria eligibility script, will be submitted to 
the IRB for review and written approval.  
 
The investigator must submit and obtain approval from the IRB for all subsequent 
amendments to the protocol, informed consent documents and other study 
documentation referenced above. The investigator will be responsible for obtaining IRB 
approval of the annual Continuing Review throughout the duration of the study.  
 
In addition, CHOP and PITT will request an IRB waiver to review the urine lab results 
and medical health record to preliminarily screen a prospective subject for study 
eligibility prior to consent.  
 
The investigator will notify the IRB of serious adverse events, protocol violations, and 
unanticipated problems. 
 
Changes to the protocol must be submitted to NIAID for review and approved by the IRB 
prior to being instituted. A parent or legal guardian of the subject or where applicable the 
child (age seven or older) must sign written informed consent before the subject 
undergoes any study procedures. The IRB registration will be submitted to DMID. 
15.3 Informed Consent Process 
Physicians at participating clinical recruiting sites will identify subjects with UTIs, inform 
the parent(s)/guardian(s) of the study, share the SCOUT Study informational pamphlet, 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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and request their permission to be contacted by a study team member if they are 
interested in participating.  
 
The children’s families will be given a SCOUT information pamphlet when their physician 
first tells them about the study when they initially present with UTI symptoms; the Study 
Coordinator will tell them more about the study and answer any questions that they 
might have when he/she calls to screen. If the Study Coordinator obtains verbal consent 
for screening from the parent(s)/guardian(s), the Study Coordinator will administer a brief 
symptom questionnaire. If interested, an enrollment visit will be scheduled.  At the 
enrollment visit subjects will be given comprehensive information with the informed 
consent form and the Study Nurse/Nurse Practitioner/Physician will go over the study 
procedures with them and answer any questions that they might have before they sign 
the consent form. Ample opportunity will be made for the Study Nurse/Nurse 
Practitioner/Physician and the subject and their parent(s)/legal guardian(s) to share 
information and ask questions. Informed consent is an ongoing, interactive process that 
is initiated when the discussion regarding participation on the study begins and 
continues throughout study participation. The Study Nurse/Nurse Practitioner/Physician 
will discuss the study’s purpose, procedures, timeframe, risks, potential benefits, and the 
rights of study participants with the child and their parent/legal guardian, to help the 
subject and their parent(s)/legal guardian(s) make educated decisions about whether to 
begin or continue participation in the trial. Informed consent will be obtained for each 
study subject prior to the conduct of study procedures. The SCOUT Study Nurses/Nurse 
Practitioners/Physicians will be well versed on the study protocol as well as on UTIs and 
will be able to thoroughly explain the study to the children’s families as well as answer 
any questions or concerns that they might have.  
 
The written consent document, signed by the child’ parent(s) or legal guardian(s) will 
describe potential risks and benefits of study participation as well as the responsibilities 
of the study participants, parents or legal guardians, and investigators, as well as give 
the parents/guardians an opportunity to consent or decline for the future use of stool 
samples collected throughout the study. This consent document is written in language 
understandable to the adult providing consent as the child’s responsible representative. 
The SCOUT Study will require the consent of only one parent or legal guardian to enroll 
the child in the study (45 CFR §46.408). In addition, age-appropriate assent will be 
obtained from those children seven years or older.  The original signed informed consent 
form and assent (if applicable) will be retained in the medical chart and a copy will be 
given to the subject.  
 
Participation in the SCOUT Study is voluntary. Subjects may withdraw consent at any 
time throughout the course of the study. The acquisition of informed consent will be 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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documented in the participant’s medical records, as required by 21 CFR 312.62.  .  The 
rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in 
this study.  
15.3.1 Informed Consent/Assent Process (in Case of a Minor) 
For this study, all of our subjects will be under the age of 18 years old, therefore their 
parent(s) or legal guardian(s) will be asked to sign the informed consent form. Written 
consent will be obtained from the subject after all questions and discussions have been 
completed. The National Commission for Protection of Human Subjects of Biomedical 
and Behavioral Research established age seven as a reasonable minimum age for 
involving children in some kind of assent process.  Therefore, age-appropriate assent 
will be obtained from those children seven years or older.  
 
The study does not involve any other special class of subjects. 
 
15.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
There are no exclusions. 
15.5 Payment to Subjects/Families 
All subjects (CHOP and PITT) will be compensated for their time and expenses at $25 
per study visit for a total of $75 for the three study visits. 
15.6 Subject Confidentiality 
CHOP and PITT will institute strict procedures to maintain subject confidentiality.  No 
personal information, such as names, contact information, social security numbers, etc. 
will be stored in the database managed by the CHOP-Westat BDMC. Subject 
confidentiality will be maintained by the investigators and the study teams, and by all 
administrators who are part of the study. Confidentiality will be maintained according to 
ICH E6; 4.8.10, part O “Records identifying the subject will be kept confidential and, to 
the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available. If the results of the study are published, the subject’s identity will remain 
confidential.” 
 
Information such as dates of birth and dates of events will be stored in the database by 
SCOUT Study ID number. Physical files linking study ID numbers to personal 
information will reside in locked files in the office of the principal investigator or the Study 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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Coordinator at the clinical site where the subject is enrolled.  Any publications or 
presentations resulting from this work will not identify study subjects by name, but will 
only present aggregate data.   
 
Subjects will not be identified in any published reports of this study. All records will be 
kept confidential to the extent provided by federal, state and local law. In addition, the 
investigator shall inform participants that study monitors and other representatives of 
NIAID may inspect documents and records required to be maintained by the 
investigator. The investigator will inform the participants that NIAID representatives are 
bound by agreement and the law to maintain subject privacy and confidentiality. All 
laboratory specimens, evaluation forms, reports, and other records that leave the 
collection site will be identified only by a coded number/de-identified in order to maintain 
participant confidentiality. Personally identifiable information in electronic data 
management systems will be protected compliant with regulatory requirements and 
federal computing security requirements to preserve privacy and confidentiality. Clinical 
information will not be released without written permission of the participant, except as 
necessary for monitoring by the IRB, NIAID, and OHRP. 
 
Both CHOP and PITT have facilities available and procedures in place to ensure the 
secure storage of subject records in compliance with HIPAA regulations. All physical 
files linking study records to personal information will reside in locked filing cabinets in 
the offices of the investigative team members.  Access to these locked storage areas will 
be strictly limited to study investigators. Computers used for storage of study data will be 
password protected. Subject identifiers will be removed before entering information into 
the research database.  
 
Seattle Children’s Hospital and the University of Minnesota, the institutions conducting 
the sub-studies, will receive no identifiable patient information.  
15.7 Future Use of Stored Specimens 
All subject(s) or parent(s)/legal guardian(s) will be asked to sign the informed consent 
form and specify whether or not they agree to allow their leftover stool samples to be 
used for secondary analyses. The stool samples may be shared with other investigators 
at other institutions. The focus is on obtaining permission to analyze archived samples in 
ways not planned at the time that the initial informed consent was obtained.  
 
Those subjects that do not allow for future use of their stool samples will have their 
samples destroyed at the end of the study. Subjects who do not agree will indicate this 
on the informed consent and will have no further involvement in this study. Declining 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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consent does not in any way jeopardize participation in any other current or future 
clinical trial. 
 
All children enrolled in the SCOUT Study will have a urine specimen collected after they 
have completed their study product at their Test of Cure Study Visit (or for asymptomatic 
subjects at the Outcome Assessment Visit if unable to collect it at the TOC Visit).  These 
urine samples will only be used to determine if their UTI was adequately treated and will 
not be kept for additional studies. Genetic testing is not planned; however there may be 
future bacterial genomic testing on the subject’s stool sample.  


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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16   DATA HANDLING AND RECORD KEEPING 
16.1 Data Management Responsibilities 
The CHOP Biostatistics and Data Management Core (BDMC) facility will provide 
analytical, data management and information technology support.  
The objectivity and independence in carrying out statistical support and data 
management services is ensured through the creation and implementation of the 
Statistical Analysis Plan (SAP) and Data Management Plan (DMP).  The SAP is a 
written document describing the analyses to be performed for this study.  Before any 
analyses (including interim analyses) begin, the Protocol Biostatistician will develop the 
SAP in conjunction with other applicable project staff, following the BDMC Standard 
Operating Procedure (SOP).  The SAP addresses statistical analysis considerations 
such as: justification for the sample size; populations considered for the analysis of 
efficacy and safety; definitions of eligibility and evaluability, data handling and statistical 
methods, specifications for how to handle missing data, planned reasons for excluding 
subjects for whom data are available from analysis, summary of method of analyses, 
including statistical tests for each of the outcome measures outlined in the protocol, 
planned analyses of subgroups and project center effects; and justification for 
adjustment or lack of adjustment to the significance level for multiple comparisons. 
The BDMC data management team, led by a Clinical Data Manager (CDM), will develop 
a Data Management Plan (DMP) that provides information on study objectives; the 
scope of work; responsibilities; applicable BDMC SOPs; scheduled study visits and 
required CRFs; data handling conventions; and communication and coordination plans 
with NIAID/DMID, Principal Investigators (PIs), sites, and internal study staff. The DMP 
serves as a reference guide to the operational procedures governing the life-cycle of 
data management activities for the study. This comprehensive plan encompasses all 
data management phases and facets of the study to ensure high standards of data 
quality.  Having these data management policies and procedures documented prior to 
the start of data collection, updated as necessary during the study, and monitored for 
compliance throughout the study, ensures objectivity and independence while carrying 
out data management services. 
In addition, the BDMC data management team will assist with the design of case report 
forms (CRFs). The BDMC CRF development team will follow BDMC SOPs to design 
CRFs electronically that are user-friendly for the sites and meet the specific needs of the 
trial as defined in the protocol. These SOPs are Data Management Case Report Form 
Review and Developing Case Report Forms. CHOP will work with NIAID/DMID and the 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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PIs to develop a first draft of the CRFs. They will develop CRF completion guidelines, 
and provide training to site coordinators on how to complete CRFs. The BDMC data 
management team will set up data entry screens, program edit checks, perform 
functional testing, maintain databases, and provide user support. The CHOP-Westat 
BDMC training team will provide training to data entry staff from participating sites before 
they begin data entry in OC-Remote Data Capture (RDC) application. They will 
successfully complete this training before receiving access to the RDC production 
database. The BDMC data management team will also provide study-specific training.  
16.2 Data Capture Methods 
Data for all subjects enrolled in this study will be obtained from thirteen sources: 1) the 
clinical microbiology laboratory; 2) initial subject screening phone call; 3) the Enrollment 
Visit; 4) Test of Cure Visit on Day 11 – 14; 5) Outcome Assessment Visit Day 24 -  30; 6) 
Follow-up Call on day 38 - 44; 7) the Pittsburgh Infectious Disease Research Laboratory 
(IDRL); 8) the subject medical record; 9) urinalysis; 10) urine culture; 11) three stool 
specimens; 12) medication diary; and 13) medication usage data (medication diary).  
Since subjects will be recruited from three sources (primary care sites, in-patient units, 
and emergency department), the medical record encompasses all three sources of data.  
Data elements provided by each source are shown in the table below.  In case of 
discrepancies in data from different sources, the data source considered primary will 
take precedent.   
 
The sub-study at Seattle Children’s Hospital will analyze isolates from stool samples 
already collected as part of the SCOUT study. No additional data sources will be used 
for the sub-study.  
 
The Microbiome pilot study will analyze additional perirectal swabs, anal swabs, and 
stool specimens collected from subjects who agree to participate. Additionally, subjects 
agreeing to participate will be asked to complete a questionnaire providing data about 
feeding (breast milk, formula, timing of introduction of solid foods); tonsillectomy history; 
most recent antibiotic prescriptions (name, dose, and duration); and number of antibiotic 
courses in life.    
 
The Spectrum of Stool Bacteria sub-study will collect data on organisms that are already 
identified as part of the processing of the stool collected for the SCOUT study. No 
additional data sources will be used for the sub-study. 
 
 
 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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Table 10: SCOUT Study Data Collection  
 
 
 
 
Data 
Initial phone call 
Enrollment Study 
Visit 
TOC Study Visit 
Outcome Assessment 
Visit 
Follow-up Phone Call 
As Needed 
Pitt IDRL 
Medical Record 
AE Form 
Preliminary Study 
Eligibility 
P 
 
 
 
 
 
 
 
 
Confirmatory Study 
Eligibility 
 
P 
 
 
 
 
 
 
 
Demographics 
 
P 
 
 
 
 
 
S 
 
Medical History 
P 
P 
 
 
 
 
 
S 
 
Symptom 
Assessment 
P 
P 
P 
P 
P 
P 
 
 
P 
Clinical Evaluation 
 
P 
P 
P 
 
P 
 
S 
 
Medication History 
 
P 
 
 
 
 
 
S 
 
Concomitant 
Medications 
 
P 
P 
P 
P 
P 
 
S 
S 
AEs and SAEs 
 
 
P 
P 
P 
P 
 
 
P 
Stool Specimen 
 
P 
P 
P 
 
 
P 
 
 
Urine Culture and 
Urinalysis 
 
 
P 
 
 
P 
 
S 
 
Study product Usage 
 
 
P 
 
 
 
 
 
 
Compliance 
 
 
P 
 
 
 
 
 
 
        P-Primary source of data; S-Secondary source of data 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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The CHOP- Westat’s BDMC Technical Training Team will use Oracle Clinical (OC) 
Remote Data Capture (RDC) as the primary data collection and management system for 
this trial. This system is fully validated and compliant with all federal guidelines. The 
BDMC database development team will develop the OC-RDC database based on the 
defined data elements of the CRFs following BDMC SOP, Systems Development Life 
Cycle.  The database developers will maintain and update the database to reflect and 
track updates to the CRF modules; all of the CRF updates must be approved by the 
NIAID Division of Microbiology and Infectious Diseases (DMID) before the BDMC begins 
the database and data entry screen modification. Additional information on the security-
relevant features of the application will be added when the system is implemented in 
support of the proposed research study. The BDMC data management team will develop 
data entry guidelines and CHOP and PITT site staff will perform web-based, on-site data 
entry using the RDC application.  
Study site staff will perform web-based, on-site data entry using RDC. Users are granted 
access at the site level so that they are allowed to see only their own data. One of the 
most valuable features of RDC is its provision of immediate feedback as data are 
entered. Univariate checks such as missing data and range checks are executed upon 
data entry and provide an opportunity to correct an error or to create a discrepancy and 
proceed with data entry. Upon completion of data entry and saving a form, multivariate 
checks (such as cross form checks) are automatically executed. In addition, edit checks 
can be executed in batch mode by the user as needed. Users can also add manual 
discrepancies to a field or sections of a CRF as needed. In order to maximize accuracy 
of the data entered, BDMC will perform a manual review of data and will utilize the 
approval and verification features in RDC for quality control purposes at the sites.  
 
The CHOP-Westat BDMC Technical Training Team will provide a web-based training as 
an option for generic RDC training. In-person, instructor-led training is also available 
upon request. The generic training will focus on teaching the basic concepts and 
principles of the RDC application as they apply to the user’s role (e.g., entering data). To 
ensure that users have an opportunity to demonstrate competency in performing RDC 
tasks before accessing the actual production database, users will be assessed on two 
levels. The first level will measure the user’s comprehension of basic RDC concepts and 
principles using true/false and multiple choice questions. The second level will allow the 
user to apply these concepts in a “real world” environment with a practicum training case 
using electronic CRFs (eCRFs) similar to those used for the protocol. Using the RDC 
training database, which simulates the production environment, the user will perform 
tasks on the eCRFs just as he or she would when in the production database. While the 
training case does not contain exact duplicates of the protocol eCRFs, and therefore 
does not substitute for protocol or project-specific training, it does give users an 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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excellent opportunity to transfer and apply the common concepts and principles learned 
in training to eCRFs resembling those on the protocol. Instructors will be available via 
email and by appointment during normal business hours to assist users with any 
questions or concerns that may arise. Users must successfully pass both levels of 
assessment to receive a certificate of qualification and RDC production access. Users 
who are not successful will participate in a one-on-one remediation session with an 
instructor before retaking the assessment. 
 
Additionally, protocol specific RDC training will be provided via web-cast by the data 
management team. The data entry guidelines document is used as the basis for this 
training; instructors review the guidelines document with participants and demonstrate 
the keying of data into RDC by using actual eCRFs in a test database.  
 
The BDMC will use the validated Thesaurus Management System (TMS) module within 
OC to automatically code all direct matches of the CRF term with the preferred term from 
the dictionary. The TMS system facilitates the consistent use of dictionaries. The 
Medical Coder will manually code non-matched terms if the preferred term is obvious. 
Non-matches that cannot be coded by the Medical Coder are forwarded to the 
supervising coder for review.  Since the study subjects will be otherwise healthy normal 
children, it is difficult to know in advance how many events or medications will need to 
be coded, but it is  expected to be a relatively small number.  
16.3 Types of Data 
Data for all subjects enrolled in this study will be obtained from thirteen sources: 1) the 
clinical microbiology laboratory; 2) initial subject screening phone call; 3) the Enrollment 
study visit and, for subjects enrolled prior to Day 5, phone call verification for no fever or 
worsening of symptoms; 4) Test of Cure Visit on Day 11 – 14; 5) Outcome Assessment 
Visit Day 24 -  30; 6) Follow-up Phone Call on Day 38 - 44; 7) the Pittsburgh Infectious 
Disease Research Laboratory (IDRL); 8) the subject medical record; 9) urinalysis; 10) 
urine culture; 11) three stool specimens ; and 12) medication diary.  Study data will be 
collected on case report forms (CRF) designed for the study in an electronic data 
system. Data for this study will include safety, clinical laboratory, and outcome 
measures. 
16.4 Timing/Reports 
The CHOP Biostatistics and Data Management Core (BDMC) has developed a wide 
variety of status reports to monitor study progress. Study status of data management 
activities is provided on a frequent basis via a project status report. The report contains 
the number of CRF pages received, pages entered, pages reviewed, outstanding query 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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resolutions, and total number of subjects per site. These status reports will be made 
available to NIAID/DMID on a monthly basis. There are other possible status variables 
that NIAID/DMID might wish to monitor, and the BDMC will work with NIAID/DMID to 
define these reports.  
 
The Westat Automated Report Portal (WARP) is a web-based service designed to 
provide users with an online reporting system. WARP delivers dynamic reports driven by 
project databases, as well as static documents such as PDF and MS-Word files. 
Dynamic reports can be programmed and run on-demand. Users simply enter pre-
selected report parameters through the WARP user interface and receive dynamic 
output through their browser. Multiple output formats are available, such as HTML and 
PDF, and users can extract and download pre-programmed data via Excel files for 
additional processing. 
 
Once half the subjects have completed the study, an interim analysis for the primary 
outcome measure will be performed.   
 
At the conclusion of the study, a CD (or other media, if requested) will be sent to 
NIAID/DMID containing the following: 
• 
Clinical datasets in SAS; 
•   SAS formats and catalogs; and 
•   Summary of transmitted datasets. 
16.5 Study Records Retention 
Study data, case report forms, and regulatory documents will be kept at the sites 
throughout the duration of the study. At the conclusion of the study, the records will be 
retained at archival storage places in accordance with the applicable FDA regulations 
(21 CFR 312.62) as paraphrased below: 
1) For at least two years following the date on which the study product is approved by 
the FDA for marketing for the purposes specified in the clinical investigation; or 
2) For at least two years following the date on which the entire clinical investigation 
(not just the investigator’s part in it) is terminated or discontinued. These documents 
will be retained for a longer period, however, if required by local regulations.  No 
records will be destroyed without the written consent of the sponsor.  It is the 
responsibility of the sponsor to inform the investigator when these documents no 
longer need to be retained. 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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16.6 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical 
Practice, or protocol specific Manual of Procedures. The noncompliance may be on the 
part of the subject, the investigator, or the study site staff. If study staff is unable to 
contact a subject requiring the day 5/6 contact before the subject starts the study 
product on day 6, it will be categorized as a protocol deviation.  
 
All protocol deviations will be reported to DMID within five working days of identification 
of the protocol deviation, or within five working days of the scheduled protocol-required 
activity. All deviations from the Protocol must be addressed in the Subject Source 
Documentation. The documentation should include the reasons for the deviation and all 
attempts to prevent or correct them. Protocol deviation reports will be submitted as 
required by site IRBs.   


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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17  PUBLICATION POLICY 
Following completion of the study, the investigator will publish the results of this research 
in a scientific journal.  The DMID will review the publication prior to submission to a 
scientific journal. The International Committee of Medical Journal Editors (ICMJE) 
member journals have adopted a trials-registration policy as a condition for publication.  
This protocol will be registered on ClinicalTrials.gov by the Principal Investigator, as 
sponsored by the National Library of Medicine, to meet publication requirements by 
the ICMJE. The ICMJE defines a clinical trial as any research project that prospectively 
assigns human participants to intervention or comparison groups to study the cause-
and-effect relationship between a medical intervention and a health outcome.   
 
Authorship of publications developed from this study will be determined by Dr. Zaoutis in 
collaboration with Dr. Hoberman.  Prior to submission for publication, articles will be 
submitted to DMID for review.  
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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18 LITERATURE REFERENCES 
1. Beetz, R., May we go on with antibacterial prophylaxis for urinary tract infections? 
Pediatr Nephrol, 2006. 21: p. 5-13. 
 
2. Elder, J.S., et al., Pediatric Vesicoureteral Reflux Guidelines Panel summary report on 
the management of primary vesicoureteral reflux in children. J Urol, 1997. 157(5): 
p.1846-51. 
 
3. Cosgrove SE, Carmeli Y. The impact of antimicrobial resistance on health and economic 
outcomes. Clin Infect Dis. Jun 1 2003; 36(11):1433-1437. 
 
4. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: 
mortality, length of hospital stay, and health care costs. Clin Infect Dis. Jan 15 2006; 42 
Suppl 2:S82-89. 
 
5. Cohen ML. Epidemiology of drug resistance: implications for a post-antimicrobial era. 
Science. Aug 21 1992; 257(5073):1050-1055. 
 
6. Holmberg SD, Solomon SL, Blake PA. Health and economic impacts of antimicrobial 
resistance. Rev Infect Dis. Nov-Dec 1987; 9(6):1065-1078. 
 
7. Livermore DM. Bacterial resistance: origins, epidemiology, and impact. Clin Infect Dis. 
Jan 15 2003; 36 (Suppl 1):S11-23. 
 
8. Tenover FC. Development and spread of bacterial resistance to antimicrobial agents: an 
overview. Clin Infect Dis. Sep 15 2001; 33 Suppl 3:S108-115. 
 
9. Talbot GH, Bradley J, Edwards JE, Jr., Gilbert D, Scheld M, Bartlett JG. Bad bugs need 
drugs: an update on the development pipeline from the Antimicrobial Availability Task 
Force of the Infectious Diseases Society of America. Clin Infect Dis. Mar 1 2006; 
42(5):657-668. 
 
10. Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance 
among uropathogens causing acute uncomplicated cystitis in women. Jama. Feb 24 
1999; 281(8):736-738. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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11. Kahlmeter G. The ECO*SENS Project: a prospective, multinational, multicentre 
epidemiological survey of the prevalence and antimicrobial susceptibility of urinary tract 
pathogens-interim report. J Antimicrob Chemother. Aug 2000; 46 Suppl A:15-22. 
 
12. Gupta K, Sahm DF, Mayfield D, Stamm WE. Antimicrobial resistance among 
uropathogens that cause community-acquired urinary tract infections in women: a 
nationwide analysis. Clin Infect Dis. Jul 1 2001; 33(1):89-94. 
 
13. Qin X, Zerr DM, Weissman SJ, et al. Prevalence and Mechanisms of Broad-spectrum 
{beta}-lactam Resistance in Enterobacteriaceae: a Children's Hospital Experience. 
Antimicrob Agents Chemother. Sep 2 2008. 
 
14. Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial 
pathogens: no ESKAPE. J Infect Dis. Apr 15 2008; 197(8):1079-1081. 
 
15. Landman D, Bratu S, Kochar S, et al. Evolution of antimicrobial resistance among 
Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae in 
Brooklyn, NY. J Antimicrob Chemother. Jul 2007; 60(1):78-82. 
 
16. Zhanel GG, Karlowsky JA, Harding GK, et al. A Canadian national surveillance study of 
urinary tract isolates from outpatients: comparison of the activities of trimethoprim-
sulfamethoxazole, ampicillin, mecillinam, nitrofurantoin, and ciprofloxacin. The Canadian 
Urinary Isolate Study Group. Antimicrob Agents Chemother. Apr 2000; 44(4):1089-1092. 
 
17. Lutter SA, Currie ML, Mitz LB, Greenbaum LA. Antibiotic resistance patterns in children 
hospitalized for urinary tract infections. Arch Pediatr Adolesc Med. Oct 2005; 
159(10):924-928. 
 
18. Doganis D, Siafas K, Mavrikou M, et al. Does early treatment of urinary tract infection 
prevent renal damage? Pediatrics. Oct 2007; 120(4):e922-928. 
 
19. Metlay JP, Strom BL, Asch DA. Prior antimicrobial drug exposure: a risk factor for 
trimethoprim-sulfamethoxazole-resistant urinary tract infections. J Antimicrob 
Chemother. Apr 2003; 51(4):963-970. 
 
20. Hyle EP, Lipworth AD, Zaoutis TE, et al. Risk factors for increasing multidrug resistance 
among extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella 
species. Clin Infect Dis. May 1 2005; 40(9):1317-1324.  
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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21. Sahm DF, Thornsberry C, Mayfield DC, Jones ME, Karlowsky JA. Multidrug-resistant 
urinary tract isolates of Escherichia coli: prevalence and patient demographics in the 
United States in 2000. Antimicrob Agents Chemother. May 2001; 45(5):1402-1406. 
 
22. Lautenbach E, Tolomeo P, Mao X, et al. Duration of outpatient fecal colonization due to 
Escherichia coli Isolates with decreased susceptibility to fluoroquinolones: longitudinal 
study of patients recently discharged from the hospital. Antimicrob Agents Chemother. 
Nov 2006; 50(11):3939-3943. 
 
23. Schlager TA, Hendley JO, Bell AL, Whittam TS. Clonal diversity of Escherichia coli 
colonizing stools and urinary tracts of young girls. Infect Immun. Mar 2002; 70(3):1225-
1229. 
 
24. Stamey TA, Timothy M, Millar M, Mihara G. Recurrent urinary infections in adult women. 
The role of introital enterobacteria. Calif Med. Jul 1971; 115(1):1-19. 
 
25. Reves RR, Fong M, Pickering LK, Bartlett A, 3rd, Alvarez M, Murray BE. Risk factors for 
fecal colonization with trimethoprim-resistant and multiresistant Escherichia coli among 
children in day-care centers in Houston, Texas. Antimicrob Agents Chemother. Jul 1990; 
34(7):1429-1434. 
 
26. Reves RR, Murray BE, Pickering LK, Prado D, Maddock M, Bartlett AV, 3rd. Children 
with trimethoprim- and ampicillin-resistant fecal Escherichia coli in day care centers. J 
Infect Dis. Nov 1987; 156(5):758-762. 
 
27. Rydberg J, Cederberg A. Intrafamilial spreading of Escherichia coli resistant to 
trimethoprim. Scand J Infect Dis. 1986; 18(5):457-460. 
 
28. Fornasini M, Reves RR, Murray BE, Morrow AL, Pickering LK. Trimethoprim-resistant 
Escherichia coli in households of children attending day care centers. J Infect Dis. Aug 
1992; 166(2):326-330. 
 
29. Davies J. Inactivation of antibiotics and the dissemination of resistance genes. Science. 
Apr 15 1994; 264(5157):375-382. 
 
30. Bronzwaer SL, Cars O, Buchholz U, et al. A European study on the relationship between 
antimicrobial use and antimicrobial resistance. Emerg Infect Dis. Mar 2002; 8(3):278-
282. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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31. Goossens H, Ferech M, Vander Stichele R, Elseviers M. Outpatient antibiotic use in 
Europe and association with resistance: a cross-national database study. Lancet. Feb 
12-18 2005; 365(9459):579-587. 
 
32. Seppala H, Klaukka T, Vuopio-Varkila J, et al. The effect of changes in the consumption 
of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. 
Finnish Study Group for Antimicrobial Resistance. N Engl J Med. Aug 14 1997; 
337(7):441-446. 
 
33. Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic 
therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed 
solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. Aug 2000; 
162(2 Pt 1):505-511. 
 
34. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for 
ventilator-associated pneumonia in adults: a randomized trial. JAMA. Nov 19 2003; 
290(19):2588-2598. 
 
35. Safdar N, Maki DG. The commonality of risk factors for nosocomial colonization and 
infection with antimicrobial-resistant Staphylococcus aureus, enterococcus, gram-
negative bacilli, Clostridium difficile, and Candida. Ann Intern Med. Jun 4 2002; 
136(11):834-844. 
 
36. Hill DR, Ericsson CD, Pearson RD, et al. The practice of travel medicine: guidelines by 
the Infectious Diseases Society of America. Clin Infect Dis. Dec 15 2006; 43(12):1499-
1539. 
 
37. el Moussaoui R, de Borgie CA, van den Broek P, et al. Effectiveness of discontinuing 
antibiotic treatment after three days versus eight days in mild to moderate-severe 
community acquired pneumonia: randomised, double blind study. BMJ. Jun 10 2006; 
332(7554):1355. 
 
38. Agarwal G, Awasthi S, Kabra SK, Kaul A, Singhi S, Walter SD. Three day versus five 
day treatment with amoxicillin for non-severe pneumonia in young children: a multicentre 
randomised controlled trial. BMJ. Apr 3 2004; 328(7443):791. 
 
39. Casey JR, Pichichero ME. Metaanalysis of short course antibiotic treatment for group a 
streptococcal tonsillopharyngitis. Pediatr Infect Dis J. Oct 2005; 24(10):909-917. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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40. Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. 
Comparison of short-course (5 days) and standard (10 days) treatment for 
uncomplicated cellulitis. Arch Intern Med. Aug 9-23 2004; 164(15):1669-1674. 
 
41. Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE, et al. Treatment of acute otitis media 
with a shortened course of antibiotics: a meta-analysis. JAMA. Jun 3 1998; 
279(21):1736-1742. 
 
42. Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines for 
antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis 
in women. Infectious Diseases Society of America (IDSA). Clin Infect Dis. Oct 1999; 
29(4):745-758. 
 
43. Keren R, Chan E. A meta-analysis of randomized, controlled trials comparing short- and 
long-course antibiotic therapy for urinary tract infections in children. Pediatrics. May 
2002; 109(5):E70-70. 
 
44. Tran D, Muchant DG, Aronoff SC. Short-course versus conventional length antimicrobial 
therapy for uncomplicated lower urinary tract infections in children: a meta-analysis of 
1279 patients. J Pediatr. Jul 2001; 139(1):93-99. 
 
45. Michael M, Hodson EM, Craig JC, Martin S, Moyer VA. Short compared with standard 
duration of antibiotic treatment for urinary tract infection: a systematic review of 
randomised controlled trials. Arch Dis Child. Aug 2002; 87(2):118-123. 
 
46. Benador D, Benador N, Slosman D, Mermillod B, Girardin E. Are younger children at 
highest risk of renal sequelae after pyelonephritis? Lancet. Jan 4 1997; 349(9044):17-
19. 
 
47. Hoberman A, Wald ER, Hickey RW, et al. Oral versus initial intravenous therapy for 
urinary tract infections in young febrile children. Pediatrics. Jul 1999; 104(1 Pt 1):79-86. 
 
48. McCracken GH, Jr. Options in antimicrobial management of urinary tract infections in 
infants and children. Pediatr Infect Dis J. Aug 1989; 8(8):552-555. 
 
49. Feigin R, Cherry J, MSc, Demmler-Harrison G,  Kaplan Sheldon. Feigin and Cherry's 
Textbook of Pediatric Infectious Diseases, 6th Edition. Vol. 1. Philadelphia, PA, 2009. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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50. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th Edition. L.K. 
Pickering, editor; C.J. Baker, S.S. Long, and J.A. McMillan, associate editors. American 
Academy of Pediatrics, Elk Grove, Illinois, 2006. 
 
51. U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for Industry: Complicated Urinary 
Tract Infections and Pyelonephritis – Developing Antimicrobial Drugs for Treatment, July 
1998. 
 
52. U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for Industry: Uncomplicated 
Urinary Tract Infections and Pyelonephritis – Developing Antimicrobial Drugs for 
Treatment, July 1998. 
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
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HHSN272200900022C                                                                                                       Protocol 09-0103 
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SUPPLEMENTS/APPENDICES 
A. Schedule of Events 
B. SCOUT UTI Timeline Definitions 
C. Study product agent package inserts: Sulfatrim (TMP-SMX), Suprax (Cefixime), 
Cephalexin   
 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
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APPENDIX A: SCHEDULE OF EVENTS  
         
    
Study Coordinator Reviews for Eligibility ( ab   Medical Record Review) 
If eligible, contacts family to review study and schedule enrollment visit (EV). The Study Coordinator 
may contact parents prior to receipt of urine culture results if child is otherwise eligible. 
                -         
            
1. Informed Consent/Assent 2. Eligibility   Symptom  uestionnaire 3. Temperature Taken  4. 
Pain Assessment 5.Stool Sample  6. Blindly Randomize  7. Provide Study Meds and Med Diary 
           Day 5/6 Contact 
1. complete symptom questionnaire  
Placebo 
                 –                       
1. Symptom  uestionnaire 2. Temperature Taken  
3. Pain Assessment 4. Stool Sample 5. Collect Medication  
Bottle 6. Collect Medication Diary 7. Collect Urine Specimen 
               
1. Symptom  uestionnaire 
2. Urine Specimen for 
Urinalysis   Urine Culture 
   1 
 
 
 
  
 
 
  5  
  6 
    
   
  10  
   
  11 
  14  
 
  
  24 
  30 
 
 
  
 38 
 44 
                       
 es 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       
Identification 
Treatment 
Follow-up and  Evaluation 
       -           
-              
1. Symptom  uestionnaire  
Primary Care Clinician Notifies Patient Family about the SCOUT Study 
Obtains Permission to Contact Patient / Family 
 es 
No 
No 
 es 
Febrile or Symptomatic UTI : Antibiotic Treatment Started  
Participation Ends 
Patient Family Contacts  
Study Team 
UTI Symptoms    
Day 6-10 
                 -          
                   
1. Symptom  uestionnaire 2. Temperature Taken  
3. Pain Assessment 4. Stool Sample  
5. Collect Urine Specimen if applicable 
Treatment Failure   
UTI Symptoms    
 es 
No 
SCOUT protocol  
participation Ends 
 
Child’s family will choose to 
be seen by site non-SCOUT 
physician or their PCP for 
care, treatment, and follow-
up in communication w/ 
SCOUT PI 
               
1. Symptom  uestionnaire 2. Urine Specimen 
for Urinalysis   Culture 
If positive, Child’s family will choose to be seen 
by site non-SCOUT physician or their PCP for 
care, treatment, and follow-up in communica 
tion w/ SCOUT PI 
Recurrent Infection   
     
Visit before Day 5/6  
Visit on Day 5/6  
Subject withdraws 
or is withdrawn 
from study  
Same Abx 
Symptomatic 
Asymptomatic 
Subject is an entry 
failure and SCOUT 
participation ends.  
1. Refer to PCP   
2. Collect study 
medication 
 es 
No 
                        
1. Symptom question 
naire 2. Collect medica 
tion and diary 3. Refer to 
PCP  
Treatment Failure   
 es 
No 


“Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance”                                                                                
The SCOUT Study: Short COurse Therapy for Urinary Tract Infections in Children 
HHSN272200900022C                                                                                                       Protocol 09-0103 
9/20/2018 
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84 
 
APPENDIX B: SCOUT UTI TIMELINE DEFINITIONS 
 
DAY
 
1
Febrile or Symptomatic UTI: Start Antibiotic Treatment
Day 2-5: Enrollment Visit 
 
4
 
 
5
Day 5/6 Contact  (if Enrollment V isit occurs before day 5)  
 
6
Day 6: Start SCOUT Study product 
 
10 
Day 10: Finish SCOUT Study product 
 
 
11 
Day 11 -  14: Test of Cure Visit  
 
14 
 
15 
 
24 
Day 24 -  30: Outcom e Assessment Visit 
 
 
30 
 
38 
Day 38 – 44: Follow -up Phone Call  
 
44 
 
Treatment Failure:
A UTI that occurs
day 6 through the 
day 11 – 14  
Test of Cure Visit.
Recurrent Infection:
A UTI that occurs 
anytime after the day 
11 – 14 Test of Cure
Visit. This can include
a relapse infection or 
reinfection .

SAP_001.pdf: 
i | P a g e  
 
 
The SCOUT Study: “Short Course Therapy for Urinary Tract Infections 
in Children” 
 
Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance 
 
 
Statistical Analysis Plan  
Version 4.0 
 
 
Sponsored by: 
 
Division of Microbiology and Infectious Disease (DMID) 
 The National Institute of Allergy and Infectious Diseases 
 
DMID Protocol Number: DMID 09-0103 
DMID Funding Mechanism: Contract No. HHSN272200900022C 
 
 
 
 
 
October 8, 2013 
Revised: February 25, 2020 
 
 
 
 
 
Prepared by: 
Elizabeth A.K. Rowley, DrPH 
CHOP-Westat Biostatistics and Data Management Core 
3535 Market Street, #1042 
Philadelphia, PA 19104 
 
 


ii | P a g e  
 
Table of Contents 
Table of Contents..................................................................................................................... ii 
List of Abbreviations .............................................................................................................. iv 
1. Introduction ........................................................................................................................ 1 
2. Project Overview ................................................................................................................ 1 
2.1. Project design ............................................................................................................... 1 
2.2. Project objectives and outcomes ................................................................................. 2 
2.2.1. Primary objective .............................................................................................. 2 
2.2.2. Primary outcome ............................................................................................... 2 
2.2.3. Secondary objectives ......................................................................................... 2 
2.2.4. Secondary outcomes ......................................................................................... 3 
2.2.5. Sub-study objectives ......................................................................................... 3 
2.2.6. Sub-study outcomes .......................................................................................... 4 
2.3. Treatments ................................................................................................................... 5 
2.4. Procedures .................................................................................................................... 5 
2.4.1. Study population............................................................................................... 5 
2.4.2. Randomization and replacement ..................................................................... 6 
2.5. Definitions .................................................................................................................... 6 
2.6. Clinical evaluations ..................................................................................................... 9 
3. Statistical Considerations ................................................................................................. 11 
3.1. Statistical design ........................................................................................................ 11 
3.2. Sample size determination and power calculations ............................................... 13 
4. Statistical Analyses ........................................................................................................... 16 
4.1. Interim analysis ......................................................................................................... 16 
4.2. Final analyses ............................................................................................................. 17 
4.2.1. Descriptive analyses ....................................................................................... 17 
4.2.2. Primary/Efficacy analysis ............................................................................... 18 
4.2.3. Secondary analyses ......................................................................................... 19 
4.2.4. Sub-study analyses.......................................................................................... 21 
4.2.5. Sub-population analyses ................................................................................ 22 
4.2.6. Safety analysis ................................................................................................. 23 


iii | P a g e  
 
5. Planned Outputs ............................................................................................................... 24 
5.1. Tables  ......................................................................................................................... 24 
6. References ......................................................................................................................... 25 
7. Appendices ....................................................................................................................... 26 
7.1. SAP Table shells......................................................................................................... 26 
7.2. Consort diagram ........................................................................................................ 50 
 
 
 
 
 


iv | P a g e  
 
Abbreviations 
 
AE 
 
 
Adverse Event 
BDMC 
 
Biostatistics and Data Management Core 
CFU/mL 
 
Colony Forming Units per milliliter 
DSMB  
 
Data and Safety Monitoring Board 
ESBL  
 
Extended Spectrum Beta Lactamases 
ITT 
 
 
Intention to Treat 
NIH  
 
National Institutes of Health 
SCOUT 
 
Short COurse Therapy for Urinary Tract Infections in Children 
SAP 
 
 
Statistical Analysis Plan 
TMP-SMX 
 
Trimethoprim-Sulfamethoxazole 
TOC  
 
Test of Cure 
UTI 
 
 
Urinary Tract Infection 
 
 
 
 


1 | P a g e  
 
1. 
Introduction 
This statistical analysis plan (SAP) is based on the SCOUT study Protocol #09-0103 
(Contract No. HHSN272200900022C) version 13.0, dated September 20, 2018. The 
SAP summarizes key aspects of the study to provide context of statistical methods 
for analyzing the data and the descriptive measures to be reported. 
2. 
Project Overview 
The SCOUT study is Phase II placebo-controlled randomized clinical trial. This 
section describes the design, objectives, outcomes, and treatments of this study as 
well as the study population and randomization. The definitions used for this study 
are also listed.  
2.1 
Project design 
This is a multi-center, centrally randomized, double-blind, placebo-controlled non-
inferiority clinical trial with children ages two months (at least 36 weeks gestational 
age birth for subjects < two years of age) to 10 years with a confirmed diagnosis of 
urinary tract infection (UTI). 724 children will be enrolled over a 4.5 year period and 
stratified based on presence of fever at the initial visit and by specific antibiotic 
therapy prescribed by the original treating clinical provider. At time of enrollment, 
children will be randomized to the standard course of antimicrobial therapy arm or 
the short course antimicrobial therapy arm. After the first 5 days of primary care 
physician initiated therapy, children who were randomized to the standard-of-care 
antimicrobial therapy arm continue on the same antibiotics for 5 more days and 
children who were randomized to the short-course antimicrobial therapy arm 
receive the placebo for 5 more days (for 10 days total). 
 


2 | P a g e  
 
2.2 
Project objectives and outcomes 
The primary, secondary, and sub-study objectives and outcomes of this study are as 
follows: 
2.2.1 Primary objective 
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 test of cure (TOC) (visit Day 11-14) as 
subjects who continue to take antibiotics for an additional 5 days  (standard course 
therapy).  
2.2.2 Primary outcome 
The primary efficacy outcome is symptomatic UTI as assessed at the TOC visit (Day 
11-14). 
2.2.3 Secondary objectives    
a. 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 re-infection) at any time after TOC visit. 
b. To determine if short-course therapy compared to standard course therapy 
results in similar numbers of children with asymptomatic bacteriuria at the TOC 
visit.   
c. To determine if short-course therapy compared to standard course therapy 
results in similar numbers of children that become colonized with antimicrobial 
resistant Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) in the 
gastrointestinal tract as assessed through Day 24-30.  


3 | P a g e  
 
d. To determine if short-course therapy compared to standard course therapy 
results in similar numbers of children presenting with clinical symptoms that may 
be related to UTI prior to or at TOC visit. 
e. To determine if short-course therapy compared to standard course therapy 
results in similar numbers of children with positive urine culture prior to or at TOC. 
2.2.4 Secondary outcomes 
The secondary outcome measures are: 
a. Recurrent infection (includes a relapse UTI or a reinfection) at any time after the 
TOC visit (Day 11-14) 
b. Asymptomatic bacteriuria at the TOC visit  
c. Colonization with antimicrobial resistant E.coli and K. pneumoniae in the 
gastrointestinal tract as assessed through Day 24-30. 
d. Presentation of clinical symptoms that may be related to UTI prior to or at the 
TOC visit 
e. Positive urine culture prior to or at the TOC visit 
2.2.5 Sub-study objectives    
• To determine if E. coli and K. pneumoniae recovered from 2 or 3 stool cultures 
are more likely to be members of disease-associated subgroups within their 
respective species (E. coli phylogroups B2 and D, K. pneumoniae clusterKpI). 
• To determine if treatment-susceptible strains recovered from cultures during 
treatment (culture #1 for 5-day arm; cultures #1 or #2, 10-day arm) are more likely to 
be members of disease-associated subgroups. 
• To determine if treatment-resistant strains of either species are more likely than 
treatment susceptible strains to be recovered from cultures during treatment. 


4 | P a g e  
 
• To determine the overall prevalence of colonization with carbapenem-resistant 
Enterobacteriaceae (overall and for specific pathogens) in children after completion 
of the course of antibiotic therapy for UTI. 
• To compare the overall biodiversity of the gut microbial community, as 
measured by culture-independent marker gene sequencing at each follow-up visit 
following short-course and standard-course antibiotic exposure. 
• To compare the overall fraction of gut microbiome community represented by 
gammaproteobacteria measured by culture-independent marker gene sequencing at 
each follow-up visit following short-course and standard-course antibiotic exposure. 
• To compare the average ecological similarity between microbial communities 
within and between treatment groups at each follow-up following short-course and 
standard-course antibiotic exposure. 
• To describe the breadth of bacteria present in the stool of children receiving 
therapy for a urinary tract infection. These data will allow for comparison of aerobic 
bacteria composition in these children and present an opportunity to contrast them 
to similar data available from other pediatric patient populations. 
2.2.6 Sub-study outcomes 
The sub-study outcome measures are: 
o Presence of E.coli and presence of K. pneumoniae 
o Sub-types of E.coli (0=phylogroups A or B1, 1=phylogroups B2 or D), sub-types 
of K. pneumoniae 
o Presence of treatment-susceptible E.coli, presence of treatment-susceptible K. 
pneumoniae 
o Presence of treatment-resistant E.coli, presence of treatment- resistant K. 
pneumoniae 


5 | P a g e  
 
o Prevalence of colonization with carbapenem resistant Enterobactericiae in 
children after completion of the course of antibiotic therapy for UTI. 
o Overall biodiversity of the gut microbial community, as measured by culture-
independent marker gene sequencing. 
o Overall fraction of gut microbiome community represented by gamma-
proteobacteria measured by culture-independent marker gene sequencing. 
o Average ecological similarity between microbial communities within and 
between treatment groups. 
o Description of bacteria present on the aerobic stool cultures obtained at each of 
the three study timepoints.   
2.3 
Treatments 
Short course therapy: prescribed antibiotic (Trimethoprim-Sulfamethoxazole (TMP-
SMX), Amoxicillin-Clavulanate, Cefixime, Cefdinir or Cephalexin) for 5 days, 
followed by placebo for 5 days; 
Standard therapy: prescribed antibiotic (TMP-SMX, Amoxicillin-Clavulanate, 
Cefixime, Cefdinir or Cephalexin) for 10 days. 
2.4 
Procedures 
2.4.1 Study Population 
Children: ages two months (at least 36 weeks gestational age at birth for subjects < 
two years of age) to 10 years with a confirmed diagnosis of a urinary tract infection 
(UTI) being treated by one of four antibiotics (TMP-SMX or Amoxicillin-Clavulanate 
or Cefixime or Cefdinir or Cephalexin). Only those subjects with documented 
clinical improvement (afebrile and asymptomatic) following four-five days of initial 
antibiotic therapy will be eligible.  


6 | P a g e  
 
2.4.2 Randomization and replacement 
Children whose parents agree to participate in the study will be randomized to 
either (1) standard-of-care antimicrobial therapy (10 days of antibiotic therapy) or (2) 
short course antimicrobial therapy arm (five days of antibiotic therapy). We will 
stratify randomization within site based on (1) whether the UTI was originally 
associated with fever, and (2) the antibiotic prescribed at initiation of therapy.  
After treatment, the subjects will be followed for 38-44 days through follow-up 
phone calls and study visits. Subjects that withdraw or are withdrawn from the 
study prior to being evaluable for the primary outcome measure will be replaced. 
The study will continue until at least 652 subjects are evaluable for the primary 
outcome measure.  At least 724 subjects will be enrolled in order to reach 652 
evaluable subjects, but the total number that will be ‘enrolled / consented’ may 
exceed 724 if the study has not enrolled 652 evaluable for the primary endpoint. 
2.5 
Definitions 
Day 1: The day when subject starts antibiotic treatment. The start of SCOUT-
directed treatment is on Day 6, after five days of initial antibiotic treatment. 
Fever/Febrile: A documented temperature of at least 100.4° F or 38° C, measured 
anywhere on the body (oral, axillary, tympanic, or rectal). 
Afebrile: NO documented temperature greater than or equal to 100.4 °F or 38°C, 
measured anywhere on the body (oral, axillary, tympanic, or rectal) in the 24 hours 
prior to the enrollment visit. 
Treatment failure: 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: 


7 | P a g e  
 
I. 
The presence of at least one of the symptoms consistent with the diagnosis of 
UTI including:  
• Symptoms for all children (ages two months to 10 years): 
o fever (a documented temperature of at least 100.4 °F OR 38°C measured 
anywhere on the body)  
o dysuria  
• 
Additional symptoms for children > 2 years of age:  
o suprapubic, abdominal, or flank pain or tenderness OR 
o 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:  
o poor feeding OR 
o vomiting  
AND 
II. 
Pyuria on urinalysis 
• >10 WBC/mm3 (uncentrifuged specimen) OR 
• >5 WBC/hpf (centrifuged specimen), OR 
• Leukocyte esterase > trace on dipstick. 
AND 
III. 
Culture proven infection with a single uropathogen:  
• >5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen) OR 
• >105 CFU/mL (clean void specimen). 
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. 
Recurrent Infection: A UTI that occurs anytime after the Day 11 – 14 Test of Cure 
Visit. This can include a relapse infection or reinfection. 


8 | P a g e  
 
Asymptomatic Bacteriuria: Asymptomatic Bacteriuria is defined in any SCOUT 
subject by: 
(1) Absence of symptoms attributable to UTI including fever AND/OR the following: 
• Symptoms for all children (ages two months to 10 years): 
o fever (a documented temperature of at least 100.4 °F OR 38°C 
measured anywhere on the body)  
o dysuria  
• 
Additional symptoms for children > 2 years of age:  
o suprapubic, abdominal, or flank pain or tenderness OR 
o 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:  
o poor feeding OR 
o vomiting 
      AND 
(2) A positive urine culture  
• 5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen) OR 
•  >105 CFU/mL (clean void specimen). 
Antibiotic Resistance: Resistance against amoxicillin-clavulanate, TMP-SMX or 
evidence of ESBL production.  
Multiple Drug Antibiotic Resistance: Resistance to two or more agents (this 
includes resistance against amoxicillin and amoxicillin-clavulanate). 
 K. pneumoniae Multiple Drug Antibiotic Resistance: Resistance to either two or 
more of the three agents (TMP-SMX, amoxicillin-clavulanate, cefixime, or 
cephalexin) that the SCOUT Study will test (excluding amoxicillin resistance). 
2.6 
Clinical evaluations 


9 | P a g e  
 
Subjects will be seen by a clinician for three study visits: 
1. Enrollment visit (Day 2-6) 
2. Test of Cure visit (Day 11-14) 
3. Outcome assessment visit (Day 24-30) 
Subjects enrolled prior to Day 5 of their prescribed medication will be verified as 
afebrile and with no worsening of conditions on Day 5 or prior to receiving the first 
dose of SCOUT therapy on Day 6.  In addition, subjects will be contacted by phone at 
the end of the study period on the Follow-up Phone Call (Day 38 - 44). Clinical 
evaluations at each visit will be as follows: 
Day 2-6 (any time after initiation of antibiotic treatment but prior to starting the 
sixth day of study treatment):  
To confirm eligibility including clinical improvement (afebrile and asymptomatic) a 
pain assessment will be performed checking for any suprapubic, abdominal, or flank 
pain or tenderness.  If a study RN receives a report of a UTI symptom at a study 
visit, he/she will inform the parent/guardian that the child should be seen by a 
clinician licensed to diagnose and treat the UTI. If this occurs at the enrollment visit, 
the child will be excluded from the study and will be referred back to the PCP who 
initially treated the child.  
Confirmation is obtained by study staff that the subject remains afebrile with no 
worsening of symptoms on Day 5-6 (prior to taking the first dose of SCOUT therapy 
on Day 6) for subjects enrolled prior to Day 5.  Any volunteer that develops a fever 
or worsening of symptoms will be withdrawn from the study and considered an 
entry failure.   
Day 11 -14 Test of Cure Post Treatment Visit (one – four days after completing the study 
product: 
The child will be clinically assessed for the presence of UTI symptoms and a urine 
specimen will be collected for test of cure. If a study RN receives a report of a UTI 


10 | P a g e  
 
symptom at the Test of Cure visit, he/she will inform the parent/guardian that the 
child should be seen by a clinician licensed to diagnose and treat the UTI. The RN 
will document the symptom on the appropriate case report form and will contact a 
study physician to arrange follow-up visit. 
Day 24 - 30 Outcome Assessment Visit (14-20 days following study product 
completion):  
The child will be clinically assessed for the presence of UTI symptoms. If a urine 
specimen could not be collected at the Day 11 – 14 TOC Visit for asymptomatic 
subjects, another attempt to collect a urine sample at this visit will be made. If a 
study RN receives a report of a UTI symptom at the Outcome Assessment visit, 
he/she will inform the parent/guardian that the child should be seen by a clinician 
licensed to diagnose and treat the UTI. The RN will document the symptom on the 
appropriate case report form and will contact a study physician to arrange follow-up 
visit. 
Day 38 - 44 Follow-up Phone Call (28-34 days after completing the study product):  
Subjects will be asked regarding presence or absence of UTI symptoms, if they 
sought medical care for possible recurrence of UTI, and to report any inter-current 
illnesses. 
 
3. 
Statistical Considerations 
3.1 
Statistical design  
This is a prospective, stratified, randomized, double-blind, placebo-controlled non-
inferiority clinical trial with standard-of-care antimicrobial therapy as arm 1 and 
short-course antimicrobial therapy placebo-controlled as arm 2.  
Primary objective 


11 | P a g e  
 
To determine if halting antimicrobial therapy in children who have exhibited clinical 
improvement 5 days after starting antibiotic therapy (short course therapy) have the 
same failure rate (symptomatic UTI) through TOC (visit Day 11-14) as subjects who 
continue to take antibiotics for an additional 5 days  (standard course therapy). 
Secondary objectives 
a. To determine if short-course therapy compared to standard course therapy 
results in similar numbers of children experiencing a recurrent infection (relapse 
and reinfection) at any time after the TOC visit (Day 11-14). 
b. To determine if short-course therapy compared to standard course therapy 
results in similar numbers of children with asymptomatic bacteriuria at the TOC 
visit.   
c. To determine if short-course therapy compared to standard course therapy 
results in similar numbers of children that become colonized with antimicrobial 
resistant Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) in the 
gastrointestinal tractas assessed through outcome assessment visit (Day 24-30).  
d. 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 prior to or at the TOC visit. 
e. To determine if short-course therapy compared to standard course therapy 
results in similar numbers of children with positive urine cultures prior to or at 
the TOC visit. 
Sub-study objectives 
• To determine if E. coli and K. pneumoniae recovered from 2 or 3 stool cultures 
are more likely to be members of disease-associated subgroups within their 
respective species (E. coli phylogroups B2 and D, K. pneumoniae clusterKpI) 


12 | P a g e  
 
• To determine if treatment-susceptible strains recovered from cultures during 
treatment (culture #1 for 5-day arm; cultures #1 or #2, 10-day arm) are more 
likely to be members of disease-associated subgroups;  
• To determine if treatment-resistant strains of either species are more likely than 
treatment susceptible strains to be recovered from cultures during treatment. 
• To determine the overall prevalence of colonization with carbapenem-resistant 
Enterobacteriaceae (overall and for specific pathogens) in ambulatory children 
after completion of treatment for UTI. 
• To compare the overall biodiversity of the gut microbial community, as 
measured by culture-independent marker gene sequencing at each follow-up 
visit following short-course and standard-course antibiotic exposure. 
• To compare the overall fraction of gut microbiome community represented by 
gammaproteobacteria measured by culture-independent marker gene 
sequencing at each follow-up visit following short-course and standard-course 
antibiotic exposure. 
• To compare the average ecological similarity between microbial communities 
within and between treatment groups at each follow-up following short-course 
and standard-course antibiotic exposure. 
• To describe the breadth of bacteria present in the stool of children receiving 
therapy for a urinary tract infection. These data will allow for comparison of 
aerobic bacteria stool composition in these children and present an opportunity 
to contrast them to similar data available from other pediatric patient 
populations.   
3.2 
Sample size determination and power calculations 
The primary aim of this study is to determine whether short-course antimicrobial 
therapy (five days) is non-inferior to standard-of care antimicrobial therapy (10 


13 | P a g e  
 
days) for the treatment of UTI in children with respect to reinfection of UTI through 
TOC visit Day 11-14. The treatment failure rate under the standard of care, R0, is 
expected to be 5%. This estimate is based on data from previously published studies 
[1, 2]. The power and sample size calculations are based on the assumption that 
recurrence under the short-course therapy, RSC, will range from 5% to 9%.  
In the non-inferiority test, on which power and sample size are based, the null 
hypothesis that short-course therapy is inferior to standard-of-care therapy is tested 
against the alternative that short-course therapy is non-inferior. That is, H0: RSC > R0 + 
δ is tested against Ha: RSC ≤ R0 + δ, where δ is the “interval of equivalence,” the range 
in which the treatment failure rates of the two therapies would be considered 
clinically equivalent. We believe that an interval of equivalence of 5% would be 
clinically acceptable; a success rate of 95% for the standard-of-care therapy group 
when compared to 90% for the short-course therapy group. For all power and 
sample size calculations, the significance level (chance of incorrectly rejecting the 
null hypothesis) is α = 0.05. 
Table 1 gives the power for testing the non-inferiority hypothesis with a sample size 
of 300 evaluable subjects per arm and with equivalence intervals (i.e., δ) ranging 
from 2% to 5%. With 300 subjects per arm, there would be 87% power with RSC = 5% 
and δ = 5%. The power decreases as either the equivalence interval decreases or as 
RSC increases; in other words, as the recurrence rates of the two regimens become 
more similar, large sample sizes are required to discriminate between them. 
Table 2 gives the sample sizes required to obtain 80% power with the same 
parameters for RSC and δ. A sample size of 235 per arm is sufficient for 80% power 
with RSC = 5% and δ = 5%, while larger sample sizes are required for larger values of 
RSC or smaller values of δ. Finally, Table 3 gives the sample sizes required to obtain 
90% power; a sample size of 326 subjects per arm would be required for 90% power 
with RSC = 5% and δ  = 5%. 


14 | P a g e  
 
 
Table 1: Power (%) for comparing standard and shortened treatment for UTI 
 
Notes: Values for power in the table are given in percent and were calculated for comparing rates of 
recurrence between standard and shortened treatment for UTI, with sample sizes of 300 per arm and 
an assumed significance level of 0.05. The assumed recurrence rate for standard treatment is 5%. As 
an example, if the actual recurrence rate for shortened treatment is 6%, there is 28% power for finding 
non-inferiority with an equivalence interval of 3%. However, the power increases to 69% with an 
equivalence interval of 5%. 
 
 
 
 
 
 
 
Table 2: Sample sizes for 80% power for non-inferiority of shortened vs. standard 
UTI antibiotic regimen 
 
This table gives sample sizes PER ARM for achieving 80% power for testing non-inferiority under the 
given values for recurrence rates and equivalence intervals. The significance level is assumed to be 
0.05. The assumed recurrence rate for standard treatment is 5%. As an example, 653 study 
participants per arm (1,306 total) would be required for 80% power if the recurrence rate for the 
standard of care and shorted regimens were both 5%, with an equivalence interval of 3%. 
 
5% 
6% 
7% 
8% 
9% 
2% 
30 
13 
– 
– 
– 
3% 
51 
28 
12 
– 
– 
4% 
72 
48 
27 
12 
– 
5% 
87 
69 
46 
25 
12 
Interval of  
equivalence 
Recurrence rate under shortened treatment 
5% 
6% 
7% 
8% 
9% 
2% 
1,469   
6,424   
– 
– 
– 
3% 
653   
1,606   
6,962   
– 
– 
4% 
368   
714   
1,741   
7,488   
– 
5% 
235   
402   
774   
1,872   
8,001   
Interval of  
equivalence 
Recurrence rate under shortened treatment 


15 | P a g e  
 
Table 3: Sample sizes for 90% power for non-inferiority of shortened vs. standard 
UTI antibiotic regimen 
 
This table gives sample sizes PER ARM for achieving 90% power for testing non-inferiority under the 
given values for recurrence rates and equivalence intervals. The significance level is assumed to be 
0.05. The assumed recurrence rate for standard treatment is 5%. As an example, 509 study 
participants per arm (1,018 total) would be required for 90% power if the recurrence rate for the 
standard of care and shortened regimens were both 5%, with an equivalence interval of 4%. 
 
Based on these calculations, we propose a sample size of 326 per arm. However, this 
value must be adjusted upwards to offset loss to follow-up.  It is expected that loss 
to follow-up will be minimal in this study. Because the study is of short duration, we 
are hopeful that we will be able to follow virtually all subjects to study completion. 
However, some study participants will not return for the follow-up visits to 
determine the primary endpoint. Furthermore, some percentage may need to 
disrupt or discontinue study treatment, or may not have the endpoint determined 
due to problems with specimens or laboratory processing. Altogether, these factors 
may reduce the sample size by as much as 10%. Thus we propose to increase the 
sample by approximately 11% to offset this sample size reduction, resulting in the 
final proposed sample size of 362 study participants per arm. 
4. 
Statistical Analyses 
The methods for the planned statistical interim analysis including the timing of the 
interim analysis, the scope of the interim analysis (a description of which endpoints 
will be analyzed), and the methods or statistical tests that will be used in the interim 
5% 
6% 
7% 
8% 
9% 
2% 
2,034     
8,898     
– 
– 
– 
3% 
904     
2,225     
9,643     
– 
– 
4% 
509     
989     
2,411     
10,371     
– 
5% 
326     
557     
1,072     
2,593     
11,082     
Interval of  
equivalence 
Recurrence rate under shortened treatment 


16 | P a g e  
 
analysis are described. The general description of the planned final analysis is 
provided.  
4.1 
Interim Analysis 
After half of the subjects (373 subjects) have enrolled, an interim analysis for the 
primary endpoint of treatment failure rate will be performed. This efficacy analysis 
will test the null hypothesis that the treatment failure rate under short-course 
therapy is less than or equal to that of standard-of-care therapy; the alternative 
hypothesis is that the failure rate under short-course therapy is greater than using 
standard-of-care therapy. This test will be one-sided test of hypothesis of equal 
treatment failure rates between the short-course therapy and standard-of-care 
therapy with α=0.05. We will calculate the difference in treatment failure rates 
between short-course therapy and standard-of-care therapy, and a one-sided 95% 
lower confidence limit using normal approximation for large samples. If the lower 
confidence limit exceeds zero, we will conclude that short-course therapy has a 
significantly higher failure rate than standard-of-care therapy. Since the interim 
analysis is for superiority of standard-of-care therapy and the final efficacy analysis 
is for non-inferiority of short-course therapy, there is no impact of the interim 
analysis on the Type I error of the final efficacy analysis and thus no adjustments to 
the significance level are required. 
In addition, conditional power estimates may be calculated.  The conditional power 
analysis is a re-assessment of the power given the results of the study to date. If the 
recurrence rate for short course therapy is smaller than expected relative to standard 
therapy, then there would be high conditional power; if the recurrence rate for short 
course therapy is greater than expected relative to standard therapy, then there 
would be lower power than initially expected. The need for this analysis will be 


17 | P a g e  
 
decided in conjunction with the DSMB, along with other data to be presented to the 
DSMB.  
4.2 
Final analyses 
The data analysis will consists of several parts. First, descriptive and baseline 
characteristics will be generated for outcome measures for the purpose of describing 
the study population and comparing the two study arms at baseline. Second, the 
primary and secondary analyses will be conducted. Finally, primary and secondary 
outcome measures will be compared between various subgroups of the study 
participants to assess potential interactions with treatment effects. Details are 
provided below. 
4.2.1 Descriptive analyses 
Standard descriptive statistics will be used to describe subjects’ baseline 
characteristics and study outcome measures overall and within each treatment 
group. Summary statistics such as means, standard deviations, medians, and ranges 
will be produced for continues variables. Frequency counts and percentage will be 
generated for describing variables that are dichotomous or polytomous in nature.  
The balance of baseline measures between short-course therapy group and 
standard-of-care therapy group will be compared using two-sample t-tests for 
normally distributed data or, the Mann-Whitney test for non-normally distributed 
data and using chi-square tests for categorical variables (Table 1 and 2 in Section 7.1). 
4.2.2 Primary/Efficacy analysis 
The primary endpoint of this study is the proportion of children experiencing 
treatment failure (symptomatic UTI) at the TOC visit (Day 11-14).  


18 | P a g e  
 
The primary analysis will follow intent-to-treat (ITT) principles, with subjects 
analyzed according to randomized treatment assignment (Table 3 in Section 7.1). In 
addition, a “per-protocol” analysis will be performed; the per-protocol analysis 
would include only subjects who were adherent to their assigned study regimen and 
completed more than 80% of the prescribed dose (Table 4 in Section 7.1). All subjects 
taking at least one dose of study treatment between Day 6 and Day 10 who have 
been evaluated for treatment success at TOC visit or have failed before TOC will be 
included in the ITT analysis (See Table 4 below).  
The primary analysis will be a non-inferiority test comparing the proportion of 
children with symptomatic UTIs at the TOC visit between two treatment arms to 
evaluate whether the difference is within the 5% equivalence interval. This test will 
be conducted by calculating the one-sided 95% upper confidence limit for the 
difference in symptomatic UTI (treatment failure) rates between the short-course 
and standard-of-care therapies. If this limit is less than or equal to the equivalence 
interval (0.05), then we will conclude that short course therapy is not inferior to 
standard therapy.  Subjects with asymptomatic bacteriuria or who are asymptomatic 
with a positive culture including pyuria will NOT be considered treatment failures 
for the primary outcome measure.  
Table 4: SCOUT Study Medication Dosage Adherence 
Antibiotic Drug 
Antibiotic Dosage 
80% of Expected 
Doses 
Trimethoprim-
Sulfamethoxazole 
 (TMP-SMX) 
8 mg/kg/day of Trimethoprim in 2 
divided doses,  
Max 160mg BID Trimethoprim 
 Eight doses 
 
Amoxicillin-
Clavulanate 
45 mg/kg/day in 2 divided doses, 
Max 875 mg Q12H 
 Eight doses 
Cefixime 
8 mg/kg/day in 1 dose, Max 400 mg 
Four doses 
Cephalexin 
50mg/kg/day in 3 divided doses 
Twelve Doses 
 


19 | P a g e  
 
4.2.3 Secondary analysis 
The secondary endpoints include: 
a. The proportion of children experiencing a recurrent urinary tract infection at any 
time after the TOC visit. 
b. The proportion of children with asymptomatic bacteriuria at the TOC visit. 
c. The proportion of children that develop the gastrointestinal colonization of 
antimicrobial resistant Escherichia coli (E. Coli) and Klebsiella pneumoniae (K. 
Pneumoniae) assessed through Outcome Assessment visit (Day 24-30).  
d. The proportion of children presenting with clinical symptoms that may be 
related to UTI prior to or at the TOC visit. 
e. The proportion of children with positive urine culture prior to or at TOC visit. 
 The secondary analysis for recurrent infection (Table 5 in Section 7.1), asymptomatic 
bacteriuria (Table 6 in Section 7.1), presenting with clinical symptoms (Table 7 in 
Section 7.1), and positive urine culture (Table 8 in Section 7.1) (Endpoints a, b, d and e), 
will include conventional tests to evaluate whether the proportions between two 
treatment arms are equal. These tests will be conducted by calculating the two-sided 
95% confidence limit for the difference between the short-course and standard-of-care 
therapies.  Analyses will be performed on per-protocol population, with appropriate 
exclusions of treatment failures.  Details of these exclusions are shown in Section 5.1. 
 
The secondary analysis for proportion of children that become colonized with 
antibiotic-resistant E. coli and Klebsiella pneumoniae assessed through Outcome 
Assessment visit (Day 24-30) (Endpoint c) will consist of two-sample tests for 
differences between proportions, using a chi-square test at significance level of 0.05 
(Table 9 in Section 7.1). We hypothesize that children with short-course therapy will be 
less likely to become colonized with emergent antibiotic-resistant E. coli and K. 


20 | P a g e  
 
pneumoniae. These analyses will examine whether antibiotic resistance after enrollment 
emerges differently between the short course and standard of care arms.  First, a 
summary of antibiotic resistance present at enrollment, TOC and Outcome Assessment 
among the per-protocol population excluding treatment failures with a sample at TOC 
(Population 4) will be presented (Table 9 in Section 7.1).   
 
Emergent antibiotic resistance will be defined as follows: 
Among Population 4 (per-protocol population excluding treatment failures without 
TOC sample), define an indicator for emergent antibiotic resistance at TOC and 
Outcome Assessment.  A child would have emergent antibiotic resistance if they 
1. Had no antibiotic-resistant E.coli or K.pneumoniae at enrollment but one or both 
are now present. OR 
2. Had either antibiotic-resistant E.coli or K.pneumoniae at enrollment but now the 
other antibiotic-resistant organism is present OR 
3. Had antibiotic-resistant E.coli and/or K.pneumoniae at enrollment, but have now 
developed resistance to new antibiotics in either organism. 
 
Emergent antibiotic resistance will be examined by treatment arm in Table 10.  We also 
want to show which antibiotics the organism showed resistance (ceftazidime, 
amoxicillin-clavulanate, TMP-SMX, or ampicillin).  Prior to unblinding, patterns of 
multiple resistance will be summarized and if there are a few very common patterns 
they will also be included in this table (Table 11 in Section 7.1).   
 
Longitudinal models such as mixed-effects logistic regression models and logistic 
regression models with generalized estimating equation (GEE) will be explored to 
analyze the repeated outcome of emergent antibiotic resistance. 
 


21 | P a g e  
 
In some cases, subjects who experienced treatment failure will not be evaluable for the 
secondary objectives. Specifically: 
• Recurrent infection: Subjects with treatment failures will not be evaluable for 
recurrent infection. 
• Asymptomatic bacteriuria: subjects with treatment failure will be evaluable (all will 
be negative for asymptomatic bacteriuria – by definition, treatment failures are 
symptomatic so cannot be considered to have asymptomatic bacteriuria). 
• Colonization: Generally, subjects with treatment failure will not be evaluable for 
colonization. However, one exception would be that if the child completes the 
Test of Cure visit but is a treatment failure, we collect a stool specimen at that 
visit and thus will have a specimen to evaluate for colonization with resistant 
bacteria. 
• Clinical symptoms: subjects with treatment failure will be evaluable (all will be 
positive for clinical symptoms). 
• Positive Cultures: subjects with treatment failure will be evaluable (all will have 
positive cultures). 
4.2.4 Sub-study analyses 
Sub-study endpoints include: 
1. The proportion of patients with E. coli detected and the proportion of patients 
with K. pneumoniae detected within each treatment arm. 
2. The proportions of sub-type 0 (phylogroups A or B1) or sub-type 1 (phylogroups 
B2 or D) among patients with E. coli detected and among patients with K. 
pneumoniae detected within each treatment arm. 
3. The proportions of patients with treatment-susceptible E. coli among patients 
with E.coli detected and the proportions of patients with treatment-susceptible K. 


22 | P a g e  
 
pneumoniae among patients with K. pneumoniae detected within each treatment 
arm. 
4. The proportion of treatment-resistant E. coli among the patients with E.coli 
detected and the proportion of treatment-resistant K. pneumoniae among the 
patients with K. pneumonia detected within each arm. 
5. The proportion of colonization with carbapenem resistant Enterobactericiae in 
children after completion of the course of antibiotic therapy for UTI within each 
treatment arm. 
6. Overall biodiversity of the gut microbial community, as measured by culture-
independent marker gene sequencing. 
7. Overall fraction of gut microbiome community represented by 
gammaproteobacteria measured by culture-independent marker gene sequencing. 
8. Average ecological similarity between microbial communities within and 
between treatment groups. 
The analysis plan for the sub-studies are designed and executed outside of the 
SCOUT protocol by the Principal Investigators. The analysis for the sub-study is not 
discussed further in this SAP. 
4.2.5 Sub-population analyses  
Treatment effects for the primary and secondary endpoints will be estimated as 
differences between proportions and compared for subpopulations defined by age 
(defined initially as less than 3 years old, 3 to 6 years old, and 7 to 10 years old), 
febrile or non-febrile UTI, type of originally prescribed antibiotic, and site. First, 
proportions will be tabulated as two-sample comparisons and chi-square tests for 
treatment differences in the endpoints within subgroups will be calculated (Table 12-


23 | P a g e  
 
17 in Section 7.1). Factors where significant differences are observed will be further 
assessed using logistic regression analysis (Table 18-23 in Section 7.1). Goodness of fit 
test will be reported for model checking. Treatment-by-subpopulation interactions 
will be tested using likelihood ratio tests. The power of these comparisons is 
expected to be low for both primary and secondary endpoints. The study is only 
likely to detect marked differences in treatment effects in these subpopulations. 
These analyses will use only the per-protocol population with appropriate 
exclusions (see Section 5.1). Because these analyses are exploratory, significance 
level at 0.05 will be used.  
4.2.6 Safety Analysis 
Safety will be evaluated by the collection and analysis of data on (S)AEs. All (S)AEs 
will be reported, regardless of their relationship to study product (Table 24 in Section 
7.1). The number of subjects with adverse events and the number of adverse events 
will be reported by body system and by treatment arm (Table 24A-B in Section 7.1). 
(S)AEs results (the number of subjects with adverse event and the number of 
adverse events) will be compared by treatment arm, with statistical tests for 
differences in proportion of subjects with serious adverse events between study 
arms. These analyses will use the ITT population and two-sided tests with 
significance level of 0.05 (Table 25A in Section 7.1). 
Missing Data: Initially we will assess the extent and pattern of missing data using 
frequencies and cross-tabulations. If data are missing for only a few cases (5% or 
less), then data analysis will be conducted only on study participants with complete 
data.  However, when such a strategy would result in loss of data from a substantial 
proportion of participants (i.e., 20%) or would lead to biased or inaccurate results, 
then sensitivity analysis or some form of imputation will be performed.  The form of 


24 | P a g e  
 
imputation used will depend on the nature of the data that are missing. If data are 
missing for primary endpoint (treatment failure), frequencies for missing data by 
center, patient characteristic (clinical and demographic), and medication used will 
be examined. If there are significant associations of missingness with any of these 
characteristics, we would consider intent-to treat analysis with imputation methods 
such as regression technique, hot-deck, or best/worst case (for binary outcomes) and 
choose the one that would be most appropriate for type of missing data pattern 
(missing at random). If there is partial follow-up, that partial data might allow us to 
do an imputation. The imputation will be employed if there is a clear evidence of 
bias due to missing data. Sensitivity analyses will be performed to assess how 
sensitive results are to reasonable changes in the assumptions that are made for 
missing data. 
 
To be considered evaluable a child must meet (a) below and one of (b) , (c) or (d): 
 (a) have taken study medication, AND; 
(b) complete the Test of Cure visit, OR; 
(c) have prior evidence of a treatment failure; 
(d) answered YES to OS #3 (The Off Study CRF Question #3 is “Was a Test of 
Cure visit completed (or an interim visit if the subject was symptomatic prior to Test of 
Cure)?”). 
  
 
 


25 | P a g e  
 
5. 
Planned Outputs 
5.1 
Tables 
 Definition of populations 
 Population 1: All  subjects taking at least one dose of study treatment between 
Day 6 and Day 10 who have been evaluated for treatment success at TOC or have 
failed prior to TOC (ITT population) 
 Population 2: The enrolled subjects who were adherent to their assigned study 
regimen and completed more than 80% of the prescribed dose between Day 6 
and Day 10 (per-protocol population)  
 Population 3:  Subjects in population 2 who did not experience a treatment 
failure.   
 Population 4: Subjects in population 2 who have a stool sample at TOC visit.   
Some treatment failures will not have a sample collected at TOC because they 
failed prior to TOC.  Treatment failures without the sample at TOC would be 
excluded from population 4.   
 Definition for a subject having primary endpoint 
The primary endpoint of this study is the proportion of children experiencing 
treatment failure (symptomatic UTI) at the TOC visit (Day 11-14). 
 Data handling 
 Treat blanks and “.” as missing unless specified otherwise.   
6. 
References 
1. Keren R, Chan E. A meta-analysis of randomized, controlled trials comparing 
short- and long-course antibiotic therapy for urinary tract infections in children. 
Pediatrics. May 2002; 109(5):E70-70. 


26 | P a g e  
 
2. Hoberman A, Wald ER, Hickey RW, et al. Oral versus initial intravenous therapy 
for urinary tract infections in young febrile children. Pediatrics. Jul 1999; 104(1 Pt 
1):79-86. 
 
 


27 | P a g e  
 
7. 
Appendices 
7.1 
SAP Table shells 
Table 1.  Randomization review 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
Presence of fever 
 
 
              Yes 
 
 
              No 
 
 
Antibiotic Type 
 
 
        TMP-SMX 
 
 
   Amoxicillin-Clavulanate 
 
 
        Cefixime 
 
 
        Cefdinir 
 
 
        Cephalexin 
 
 
 
 
Note: Chi-square tests for frequencies across two treatment groups 
1. P=0.xxxx for Presence of fever versus No fever 
2. P=0.xxxx for Antibiotic Type 
 
 
 
 
 
 
 


28 | P a g e  
 
Table 2. Demographic and baseline data 
 
Arm 1:  
Standard 
Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-value 
Age, Mean ± SD 
 
 
 
2 months -35 months 
3 – 6 years 
7 – 10 years 
Gender 
 
 
 
Male 
Female 
Race/ethnicity 
 
 
 
White 
Black/African American 
Asian 
Native Hawaiian/Other Pacific 
Islander  
American Indian/Alaska Native 
Multi-Racial 
Other  
Hispanic 
Yes 
No 
 
 
 
Table 2 Specifications 
 Repeat the analysis on population 1 (ITT population) and 2 (per-protocol 
population) separately as Table 2a and 2b. 
 Table 2 was designed to show the frequencies and column percentage of subjects 
within each category unless was specified as to show means and standard deviation. 
Some categorical variables may need to be created based on numeric values. 


29 | P a g e  
 
Table 3.  Comparison of the proportion of subjects with symptomatic UTIs prior to or at 
the TOC visit for ITT population (Population 1) (Primary analysis) 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
Difference of 
proportion and one-
sided 95%  
confidence limit 
Treatment 
Failure 
 
 
 
SAS note: Using RISKDIFF ALPHA=0.10 in the TABLE STATEMENT of PROC FREQ 
procedures to calculate the difference of proportion and one sided 95% CI 
 
 
Table 4.  Comparison of the proportion of subjects with symptomatic UTIs prior to or at 
the TOC visit for per protocol population (Population 2) (Primary analysis) 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
Difference of 
proportion and one-
sided 95% confidence 
limit 
Treatment 
Failure 
 
 
 
 
 
Table 5.  Comparison of the proportion of subjects with a recurrent infection at any time 
after the TOC visit for per protocol population (Population 3) (Secondary analysis, 
Endpoint a) 
 
Arm 1:  
Standard 
Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
Difference of 
proportion and two-
sided 95% confidence 
limit 
Recurrent 
Infection 
 
 
 
  


30 | P a g e  
 
 
Table 6.  Comparison of the proportion of subjects with asymptomatic bacteriuria at the 
TOC visit for per protocol population (Population 2) (Secondary analysis, Endpoint b) 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
Difference of 
proportion and two-
sided 95% confidence 
limit 
Asymptomatic 
Bacteriuria 
 
 
 
 
 
Table 7. Comparison of the proportion of subjects with clinical symptoms that may be 
related to a UTI prior to or at the TOC visit for per protocol population (Population 2) 
(Secondary analysis, Endpoint d) 
 
Arm 1:  
Standard 
Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
Difference of 
proportion and two-
sided 95% 
confidence limit 
Clinical 
Symptoms 
 
 
 
 
 
 
 
 
 
 
 


31 | P a g e  
 
Table 8.  Comparison of the proportion of subjects with positive urine cultures prior to 
or at the TOC visit for per protocol population (Population 2) (Secondary analysis, 
Endpoint e) 
 
Arm 1:  
Standard 
Course 
Total= xxx 
                   N 
(%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
Difference of 
proportion and two-
sided 95% 
confidence limit 
Positive Urine 
Cultures 
 
 
 
 
 
 


32 | P a g e  
 
Table 9: Comparison of the proportion of children that develop the gastrointestinal 
colonization of antimicrobial resistant E. coli and K. pneumoniae through Outcome 
assessment visit (Day 24-30) for per protocol population (Population 2) (Secondary 
analysis, Endpoint c) 
 
Arm 1:  
Standard 
Course 
Total= xxx 
            
N (%) 
Arm 2:  
Short 
Course   
Total= xxx 
N (%) 
p-value 
for Chi-
square 
test 
Enrollment visit (Day 2-6)  
 
 
 
Any antibiotic-resistant E. coli 
 
 
 
Any antibiotic-resistant K. pneumoniae 
 
 
 
Any antibiotic resistance 
 
 
 
Both antibiotic-resistant E. coli and antibiotic-
resistant K. pneumoniae 
 
 
 
Multiple antibiotic-resistant E. coli      
 
 
 
Multiple antibiotic-resistant K. pneumoniae 
 
 
 
TOC visit (Day 11-14) 
 
 
 
Any antibiotic-resistant E. coli 
 
 
 
Any antibiotic-resistant K. pneumoniae 
 
 
 
Any antibiotic resistance 
 
 
 
Both antibiotic-resistant E. coli and antibiotic-
resistant K. pneumoniae 
 
 
 
Multiple antibiotic resistance to E. coli      
 
 
 
Multiple antibiotic resistance to K. pneumoniae 
 
 
 
Outcome assessment visit (Day 24-30) 
 
 
 
Any antibiotic-resistant E. coli 
 
 
 
Any antibiotic-resistant K. pneumoniae 
 
 
 
Any antibiotic resistance 
 
 
 
Both antibiotic-resistant E. coli and antibiotic-
resistant K. pneumoniae 
 
 
 
Multiple antibiotic resistance to E. coli      
 
 
 
Multiple antibiotic resistance to K. pneumoniae 
 
 
 
 
 


33 | P a g e  
 
 
Table 10:  Comparison of the proportion of children that develop emergent 
gastrointestinal colonization of antimicrobial resistant E. coli or K.pneumoniae through 
outcome assessment visit (day 24-30) for per protocol population (Population 4) 
(Secondary analysis c) 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-value 
for Chi-square 
test 
TOC visit (Day 11-
14) 
 
 
 
Outcome assessment 
visit (Day 24-30) 
 
 
 
 
 
 


34 | P a g e  
 
Table 11: Comparison of the proportion of children that develop emergent 
gastrointestinal colonization of antimicrobial resistant E. coli or K.pneumoniae by 
resistant agent through outcome assessment visit (day 24-30) for per protocol 
population (Population 4) (Secondary analysis c) 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-value 
for Chi-square 
test 
TOC visit (Day 11-
14) 
 
 
 
Emergent Resistance to 
TMP-SMX 
 
 
 
Emergent Resistance to 
Amoxicillin-clavulanate 
 
 
 
Emergent Resistance to 
Ceftazi-dime 
 
 
 
Emergent Resitance to 
Ampicillin 
 
 
 
Outcome assessment 
visit (Day 24-30) 
 
 
 
Emergent Resistance to 
TMP-SMX 
 
 
 
Emergent Resistance to 
Amoxicillin-clavulanate 
 
 
 
Emergent Resistance to 
Ceftazi-dime 
 
 
 
Emergent Resitance to 
Ampicillin 
 
 
 
 
 
 


35 | P a g e  
 
 Table 12.  Comparison of the proportion of subjects with symptomatic UTIs prior to or 
at the TOC visit for subpopulations (Population 2) (Primary endpoint) 
 
Arm 1:  
Standard 
Course 
Total= xxx 
                   N 
(%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-value for 
Chi-square 
test 
Age Group 
     2 month – 35 months 
     3 – 6 years 
     7-10 years 
 
 
 
Febrile 
     Febrile UTI 
     Non-Febrile UTI 
 
 
 
Antibiotic Type 
     TMP-SMX 
     Amoxicillin-Clavulanate 
     Cefixime 
     Cefdinir 
     Cephalexin 
 
 
 
Site 
     CHOP 
     PITT 
 
 
 
 
 
 
 
 
 
 
 


36 | P a g e  
 
 
Table 13.  Comparison of the proportion of subjects with a recurrent infection at any 
time after the TOC visit for subpopulations (Population 3) (Secondary endpoint a) 
 
 
Arm 1:  
Standard 
Course 
Total= xxx 
                   N 
(%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-value for 
Chi-square 
test 
Age Group 
     2 month – 35 months 
     3 – 6 years 
     7-10 years 
 
 
 
Febrile 
     Febrile UTI 
     Non-Febrile UTI 
 
 
 
Antibiotic Type 
     TMP-SMX 
     Amoxicillin-Clavulanate 
     Cefixime 
     Cefdinir 
     Cephalexin 
 
 
 
Site 
     CHOP 
     PITT 
 
 
 
 
 
 
 
 
 
 


37 | P a g e  
 
 
 
Table 14.  Comparison of the proportion of subjects with asymptomatic bacteriuria at 
the TOC visit for subpopulation (Population 2) (Secondary endpoint b) 
 
 
Arm 1:  
Standard 
Course 
Total= xxx 
                   N 
(%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-value for 
Chi-square 
test 
Age Group 
     2 month – 35 months 
     3 – 6 years 
     7-10 years 
 
 
 
Febrile 
     Febrile UTI 
     Non-Febrile UTI 
 
 
 
Antibiotic Type 
     TMP-SMX 
     Amoxicillin-Clavulanate 
     Cefixime 
     Cefdinir 
     Cephalexin 
 
 
 
Site 
     CHOP 
     PITT 
 
 
 
 
 
 
 
 
 


38 | P a g e  
 
 
 
 
Table 15.  Comparison of the proportion of subjects with clinical symptoms that may be 
related to a UTI prior to or at the TOC visit for subpopulation (Population 2) (Secondary 
endpoint d) 
 
 
Arm 1:  
Standard 
Course 
Total= xxx 
                   N 
(%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-value for 
Chi-square 
test 
Age Group 
     2 month – 35 months 
     3 – 6 years 
     7-10 years 
 
 
 
Febrile 
     Febrile UTI 
     Non-Febrile UTI 
 
 
 
Antibiotic Type 
     TMP-SMX 
     Amoxicillin-Clavulanate 
     Cefixime 
     Cefdinir 
     Cephalexin 
 
 
 
Site 
     CHOP 
     PITT 
 
 
 
 
 
 
 


39 | P a g e  
 
 
 
 
 
Table 16.  Comparison of the proportion of subjects with positive urine cultures prior to 
or at the TOC visit for subpopulation (Population 2) (Secondary endpoint e) 
 
 
Arm 1:  
Standard 
Course 
Total= xxx 
                   N 
(%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-value for 
Chi-square 
test 
Age Group 
     2 month – 35 months 
     3 – 6 years 
     7-10 years 
 
 
 
Febrile 
     Febrile UTI 
     Non-Febrile UTI 
 
 
 
Antibiotic Type 
     TMP-SMX 
     Amoxicillin-Clavulanate 
     Cefixime 
     Cefdinir 
     Cephalexin 
 
 
 
Site 
     CHOP 
     PITT 
 
 
 
 
 
 
 


40 | P a g e  
 
Table 17.  Comparison of Risk of emergent colonization with antimicrobial resistant E. 
coli or K. pneumoniae in Gastrointestinal Tract for Subpopulations (Population 4) 
(Secondary endpoint c)  
 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-
value
1 
 
p-
value 
2 
 
 
TOC visit 
Outcome 
visit 
 
TOC visit 
Outcome 
visit 
 
 
Age Group 
   2  – 35 months 
   3 – 6 years 
   7-10 years 
 
 
 
 
 
 
Febrile 
 Febrile UTI 
 Non-Febrile UTI 
 
 
 
 
 
 
Antibiotic Type 
   TMP-SMX 
   Amoxicillin-
Clavulanate 
   Cefixime 
   Cefdinir 
   Cephalexin 
 
 
 
 
 
 
Site 
   CHOP 
   PITT 
 
 
 
 
 
 
p-value 1 and p-value 2 will reported from Chi-square test comparing the proportions between 
sub-populations and treatment arms at TOC visit, and Outcome assessment visit, respectively.  
 
 


41 | P a g e  
 
 Table 18.  Multivariable Logistic Regression Analysis for Treatment failure 
(Symptomatic UTI at TOC visit) (Population 1) (Primary endpoint) 
 
Odds ratio 
95% CI 
p-value 
Arm 1 Standard 
Course(reference) 
Arm 2 Short Course 
 
 
 
Covariates 
 
 
 
------------ 
 
 
 
Interaction Term 
 
 
 
------------ 
 
 
 
CI: Confidence Interval 
SAS tips: SCALE=NONE in the MODEL statement of the PROC LOGISTIC procedure to 
generate deviance and Pearson chi-square for goodness of fit test. 
 
 
 
Table 19.  Multivariable Logistic Regression Analysis for Recurrent Infection at any time 
after the TOC visit (Population 3) (Secondary endpoint a) 
 
Odds ratio 
95% CI 
p-value 
Arm 1 Standard 
Course(reference) 
Arm 2 Short Course 
 
 
 
Covariates 
 
 
 
------------ 
 
 
 
Interaction Term 
 
 
 
------------ 
 
 
 
 
SAS tips: SCALE=NONE in the MODEL statement of the PROC LOGISTIC procedure to 
generate deviance and Pearson chi-square for goodness of fit test. 
 


42 | P a g e  
 
Table 20.  Multivariable Logistic Regression Analysis for Asymptomatic Bacteriuria at 
the TOC visit (Population 2) (Secondary endpoint b) 
 
Odds ratio 
95% CI 
p-value 
Arm 1 Standard 
Course(reference) 
Arm 2 Short Course 
 
 
 
Covariates 
 
 
 
------------ 
 
 
 
Interaction Term 
 
 
 
------------ 
 
 
 
 
 
Table 21.  Multivariable Logistic Regression Analysis for Symptoms that may be related 
to a UTI prior to or at the TOC visit (Population 2) (Secondary endpoint d) 
 
Odds ratio 
95% CI 
p-value 
Arm 1 Standard 
Course(reference) 
Arm 2 Short Course 
 
 
 
Covariates 
 
 
 
------------ 
 
 
 
Interaction Term 
 
 
 
------------ 
 
 
 
 
 
 
 


43 | P a g e  
 
Table 22.  Multivariable Logistic Regression Analysis for positive urine cultures prior to 
or at the TOC visit (Population 2) (Secondary endpoint e) 
 
Odds ratio 
95% CI 
p-value 
Arm 1 Standard 
Course(reference) 
Arm 2 Short Course 
 
 
 
Covariates 
 
 
 
------------ 
 
 
 
Interaction Term 
 
 
 
------------ 
 
 
 
 
Table 23.  Multivariable Logistic Regression Analysis for Risk of emergent colonization 
with any antimicrobial resistant E. coli or K. pneumoniae in Gastrointestinal Tract 
(Population 4) (Secondary endpoint c) 
 
Odds ratio 
95% CI 
p-value 
Arm 1 Standard 
Course(reference) 
Arm 2 Short Course 
 
 
 
Covariates 
 
 
 
------------ 
 
 
 
Interaction Term 
 
 
 
------------ 
 
 
 
Table 23 specifications: Repeat the analysis at enrollment visit, TOC visit, and outcome 
assessment visit separately as Table 26a, Table 26b, and Table 26c. 
 
 
 
 


44 | P a g e  
 
 
Table 24. Detailed listing for all adverse events possibly/probably related to study drug 
Study 
Arm 
Subject 
ID 
Adverse 
event 
description 
Onset 
date 
Severity Duration Relationship 
to 
medication 
Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


45 | P a g e  
 
 
Table 24A. Adverse events possibly/probably related to study drug by body system and 
treatment arm (number of subjects) 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
 
Total number of subject with adverse 
events  
 
 
 
Body as whole 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 24B. Adverse events possibly/probably related to study drug by body system and 
treatment arm (number of adverse events) 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
 
Total number of adverse events  
 
 
 
Body as whole 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 25. Adverse events possibly/probably related to study drug by treatment arm 


46 | P a g e  
 
 
Arm 1:  
Standard Course 
Total= xxx 
                   N (%) 
Arm 2:  
Short Course   
Total= xxx 
N (%) 
p-value 
Total number of subjects with AEs 
 
 
 
Total number of Adverse events 
 
 
 
Number of AEs per patient 
 
 
 
          0 
 
 
 
          1 
 
 
 
          2 
 
 
 
          3+ 
 
 
 
Severity of AE 
 
 
 
          Mild 
 
 
 
          Moderate 
 
 
 
          Severe 
 
 
 
Serious adverse events 
 
 
 
          Yes 
 
 
 
          No 
 
 
 
Relationship to medication 
 
 
 
          Related 
 
 
 
          Not related 
 
 
 
Outcome 
 
 
 
          Recovered/Resolved 
 
 
 
          Unchanged 
 
 
 
Ongoing 
 
 
 
          Yes 
 
 
 
          No 
 
 
 
 
Specifications 
 Restrict the analysis to population 1 separately by number of subjects with 
adverse event(s) (Table 24A) and number of adverse events (Table 24B). 
The test for independence of AE among two arms can be obtained using Chi-square 
test (or Fisher test if any cell expected count is less than 5). 
 


47 | P a g e  
 
7.2 
Consort diagram 
Figure 1: Consort Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Children Screening 
N=xxx 
Number of Children Eligible and 
Consent 
N=xxx 
Same Antibiotic Day 6-10 
N=xxx 
Placebo Day 6-10 
N=xxx
Symptomatic 
UTI 
Before or at 
TOC Visit 
N=xxx 
Symptomatic 
UTI 
Before or at 
TOC Visit 
N=xxx
Recurrent 
Infection  
Before or at OA 
visit 
N=xxx 
No Recurrent 
Infection 
before or at 
OA visit 
N=xxx 
No Symptomatic UTI 
Before or At TOC 
visit      
N=xxx 
No Recurrent 
Infection 
before or at 
OA visit 
N=xxx 
Recurrent 
Infection  
Before or at OA 
visit 
N=xxx 
No UTI 
(Asymptomatic 
Bacteriuria)  
N=xxx 
Recurrent Infection 
at Follow up Phone 
Call 
N=xxx 
No Recurrent 
Infection at Follow-
up Phone call  
N=xxx 
Recurrent Infection 
at Follow up Phone 
Call 
N=xxx 
No Recurrent 
Infection at 
Follow-up Phone 
call  
No UTI 
 
N=xxx 
No UTI 
(Asymptomatic 
Bacteriuria)  
N=xxx 
No UTI 
 
N=xxx 
 
No Symptomatic UTI 
Before or At TOC 
visit      
N=xxx