Clinical trial NCT02891915
Conditions: Pneumonia
Keywords: Antimicrobial Beta-Lactam Pneumonia Short Course Standard Course Therapy
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2016-12-02; Completion date: 2019-12-16
Enrollment: 385 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomized, double-blind, placebo-controlled, superiority clinical trial will test the effectiveness of short (5-day) vs.standard (10-day) course therapy in children who are diagnosed with CAP and initially treated in outpatient clinics, urgent care facilities, and emergency departments. Primary objective is to compare the composite overall outcome (Desirability of Outcome Ranking, DOOR) among children 6-71 months of age with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visit #1 (Study Day 8 +/- 2 days)

Detailed description:
This is a multi-center, randomized, double-blind, placebo-controlled, superiority clinical trial evaluating short course (5 day) vs. standard course (10 day) of oral beta-lactam antibiotic therapy (amoxicillin, amoxicillin-clavulanate, cefdinir) for treatment of CAP in children 6-71 months of age who have clinically improved prior to enrollment. The study will randomize approximately 400 enrolled subjects to one of the two study arms (approximately 200 children in each arm) in order to reach 360 subjects completing Outcome Assessment Visit 1. Subjects will be randomized (1:1) to receive either a standard course of the initially prescribed antibiotic (10 days) or a short course of the initially prescribed antibiotic (5 days) plus 5 days of matching placebo. The study will recruit potential subjects from children who are diagnosed with CAP and who are initiated on oral beta-lactam therapy by healthcare providers in EDs, outpatient clinics, and urgent care centers at the study sites. Day -5 is defined as the date on which oral beta-lactam therapy is initiated for a diagnosis of CAP. Potential subjects will be identified at any time following clinical diagnosis of pneumonia. These subjects will be assessed for eligibility and enrolled on Day -3 to -1 of their initially prescribed oral beta-lactam therapy. Subjects may also be enrolled on Day 1 (the first day of receipt of study agent) provided they have not yet received any doses of the healthcare provider-prescribed antibiotic therapy for that day. The Primary objective is to compare the composite overall outcome (Desirability of Outcome Ranking, DOOR) among children 6-71 months of age with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visit #1 (Study Day 8 +/- 2 days). The Secondary objectives are: 1) To compare the composite overall outcome (DOOR) among children 6-71 months of age with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visit #2 (Study Day 22 +/- 3 days); 2) To compare the resolution of symptoms (a component of DOOR) among children 6-71 months of age with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2; 3) To compare the clinical response (a component of DOOR) among children 6-71 months of age with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2; 4) To compare solicited events (a component of DOOR) among children 6-71 months of age with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2; 5) To compare medically attended visits to Emergency Departments (ED) or outpatient clinics, hospitalizations, surgical procedures, and receipt of non-study systemic antibiotics (components of the clinical response) among children 6-71 months of age with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2

Arms: arm 1: 200 subjects will receive a short course of the initially prescribed antibiotic for 5 days plus 5 days of matching placebo arm 2: 200 subjects will receive a standard course of the initially prescribed antibiotic( Amoxicillin, Amoxicillin-Clavulanate, Cefdinir) for 10 days
Interventions: intervention 1: Amoxicillin intervention 2: Amoxicillin-clavulanate intervention 3: Cefdinir intervention 4: Placebo
Intervention descriptions: intervention 1: Amoxicillin is an aminopenicillin antibiotic intervention 2: A fixed-ratio combination of amoxicillin trihydrate, an aminopenicillin, and potassium clavulanate, a beta-lactamase inhibitor, used to treat a broad-spectrum of bacterial infections, especially resistant strains. intervention 3: Cefdinir is a cephalosporin antibiotic used to treat bacterial infections in many different parts of the body. intervention 4: Placebo

Protocol documents:
Prot_000.pdf: 
DMID Protocol #14-0079 
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14 December 2018 
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A Phase IV Double-Blind, Placebo-Controlled, Randomized Trial to Evaluate  
Short Course vs. Standard Course Outpatient Therapy of 
Community Acquired Pneumonia in Children (SCOUT-CAP) 
 
 
 
DMID PROTOCOL NUMBER: 14-0079 
 
DMID FUNDING MECHANISM:  VACCINE AND TREATMENT EVALUATION UNIT 
IND SPONSOR: NIH/NIAID/DMID 
VTEU PRINCIPAL INVESTIGATOR: C. BUDDY CREECH, MD, MPH 
ARLG PRINCIPAL INVESTIGATORS:  W. CHARLES HUSKINS, MD, MSC 
& THEOKLIS ZAOUKIS, MD, MCSE 
 
 
VERSION NUMBER: 4.0 
14 DECEMBER 2018 


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STATEMENT OF COMPLIANCE 
 
This trial will be carried out in accordance with Good Clinical Practices (GCP) as required by the 
following: 
• 
United States Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46; 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, and 21 CFR Part 312); 
• 
International Conference on Harmonization (ICH) E6; 62 Federal Register 25691 (1997); 
• 
The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule-Final 
Modification (45 CFR Parts 160 and 164); 
• 
National Institutes of Health (NIH) Clinical Terms of Award, as applicable. 
Compliance with these standards provides public assurance that the rights, safety and well-
being of study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Subjects Protection Training. 
 


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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 United States of America (US) federal regulations and 
ICH guidelines. 
 
 
__________________________________________________________             
Site Principal Investigator Signature  
 
 
Date: _____________________ 


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TABLE OF CONTENTS 
 
 
Page 
Statement of Compliance ............................................................................................................ ii 
Signature Page .......................................................................................................................... iii 
Table of Contents ....................................................................................................................... iv 
List of Figures and Tables ......................................................................................................... vii 
List of Abbreviations ................................................................................................................. viii 
Protocol Summary ..................................................................................................................... ix 
1 
Key Roles ......................................................................................................................... 11 
2 
Background Information and Scientific Rationale.............................................................. 13 
2.1 
Background Information ........................................................................................ 13 
2.2 
Rationale .............................................................................................................. 13 
2.3 
Potential Risks and Benefits ................................................................................. 14 
2.3.1 
Potential Risks .......................................................................................... 14 
2.3.2 
Known Potential Benefits........................................................................... 14 
3 
Objectives ........................................................................................................................ 15 
3.1 
Study Objectives ................................................................................................... 15 
3.2 
Study Outcome Measures .................................................................................... 15 
3.2.1 
Primary Outcome Measures ...................................................................... 15 
3.2.2 
Secondary Outcome Measures ................................................................. 17 
3.2.3 
Exploratory Outcome Measures ................................................................ 18 
4 
Study Design .................................................................................................................... 19 
5 
Study Enrollment and Withdrawal ..................................................................................... 21 
5.1 
Subject Inclusion Criteria ...................................................................................... 21 
5.2 
Subject Exclusion Criteria ..................................................................................... 21 
5.3 
Treatment Assignment Procedures ....................................................................... 23 
5.3.1 
Randomization Procedures ....................................................................... 23 
5.3.2 
Masking Procedures .................................................................................. 23 
5.3.3 
Reasons for Withdrawal ............................................................................ 24 
5.3.4 
Handling of Withdrawals ............................................................................ 25 
5.3.5 
Termination of Study ................................................................................. 25 
6 
Study Intervention/Investigational Product ........................................................................ 26 
6.1 
Study Product Description .................................................................................... 26 
6.1.1 
Acquisition ................................................................................................. 26 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 26 
6.1.3 
Product Storage and Stability .................................................................... 28 
6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................. 29 
6.2.1 
Dosage ...................................................................................................... 29 
6.2.2 
Preparation ............................................................................................... 29 
6.2.3 
Administration ........................................................................................... 29 
6.3 
Modification of Study Intervention/Investigational Product for a Participant ........... 29 


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6.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) ... 30 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ................................................................................................................. 30 
6.6 
Concomitant Medications/Treatments ................................................................... 30 
7 
Study Schedule ................................................................................................................ 31 
7.1 
Screening ............................................................................................................. 31 
7.2 
Enrollment/Baseline .............................................................................................. 31 
7.3 
Follow-up .............................................................................................................. 33 
7.4 
Final Study Visit .................................................................................................... 34 
7.5 
Early Termination Visit .......................................................................................... 34 
8 
Study Procedures/Evaluations .......................................................................................... 36 
8.1 
Clinical Evaluations ............................................................................................... 36 
8.2 
Laboratory Evaluations ......................................................................................... 37 
8.2.1 
Clinical Laboratory Evaluations ................................................................. 37 
8.2.2 
Special Assays or Procedures ................................................................... 37 
8.2.3 
Specimen Preparation, Handling, and Shipping ........................................ 37 
9 
Assessment of Safety ....................................................................................................... 39 
9.1 
Specification of Safety Parameters ....................................................................... 39 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ........................................................................................................... 40 
9.2.1 
Adverse Events ......................................................................................... 40 
9.2.2 
Serious Adverse Events ............................................................................ 40 
9.2.3 
Procedures to be Followed in the Event of Abnormal Clinical Findings ..... 42 
9.3 
Reporting Procedures ........................................................................................... 42 
9.3.1 
Serious Adverse Events ............................................................................ 42 
9.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored 
IND ............................................................................................................ 43 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events ........................ 43 
9.5 
Halting Rules ........................................................................................................ 43 
9.5.1 
Study Halting Rules ................................................................................... 43 
9.5.2 
Individual Halting Rules (Termination of Study Product Administration) ..... 44 
9.6 
Safety Oversight ................................................................................................... 44 
9.6.1 
Data and Safety Monitoring Board (DSMB) ............................................... 44 
10 
Clinical Monitoring ............................................................................................................ 46 
10.1 
Site Monitoring Plan .............................................................................................. 46 
11 
Statistical Considerations ................................................................................................. 47 
11.1 
Study Hypothesis .................................................................................................. 48 
11.2 
Sample Size Considerations ................................................................................. 48 
11.3 
Planned Interim Analyses ..................................................................................... 48 
11.3.1 Safety Review ........................................................................................... 48 
11.3.1 Interim Analysis of Efficacy, Futility, and Safety ......................................... 49 
11.4 
Final Analysis Plan ............................................................................................... 50 
11.4.1 Primary Analysis ....................................................................................... 50 


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11.4.2 Secondary Analyses .................................................................................. 51 
11.4.3 Exploratory Analyses ................................................................................. 52 
12 
Source Documents and Access to Source Data/Documents ............................................ 53 
13 
Quality Control and Quality Assurance ............................................................................. 54 
14 
Ethics/Protection of Human Subjects ................................................................................ 55 
14.1 
Ethical Standard ................................................................................................... 55 
14.2 
Institutional Review Board .................................................................................... 55 
14.3 
Informed Consent Process ................................................................................... 55 
14.3.1 Informed Consent ...................................................................................... 55 
14.3.2 Informed Consent/Assent Process (in Case of a Minor) ............................ 56 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 56 
14.5 
Subject Confidentiality .......................................................................................... 56 
14.6 
Future Use of Stored Specimens .......................................................................... 57 
15 
Data Handling and Record Keeping ................................................................................. 58 
15.1 
Data Management Responsibilities ....................................................................... 58 
15.2 
Data Capture Methods .......................................................................................... 58 
15.3 
Types of Data ....................................................................................................... 58 
15.4 
Timing/Reports ..................................................................................................... 59 
15.5 
Study Records Retention ...................................................................................... 59 
15.6 
Protocol Deviations ............................................................................................... 59 
16 
Publication Policy ............................................................................................................. 60 
17 
Literature References ....................................................................................................... 61 
APPENDIX A – Schedule of Evaluations ................................................................................... 62 
 
 


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LIST OF FIGURES AND TABLES 
 
 
Figure 1:Study Schematic ........................................................................................................... x 
 
Table 1. Ordinal Outcome .........................................................................................................16 
Table 2: Severity of Cough ........................................................................................................17 
Table 3. Solicited Events Grading .............................................................................................17 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ARLG 
Antibiotic Resistance Leadership Group 
ATP 
According-to-Protocol 
CAP 
Community Acquired Pneumonia 
CC 
Complete Case 
CFR 
Code of Federal Regulations 
CMS 
Clinical Materials Services 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, DHHS 
DOOR 
Desirability of Outcome Ranking 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
EHR 
Electronic Health Record 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDES 
Internet Data Entry System 
IDSA 
Infectious Diseases Society of America 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-to-Treat 
MOP 
Manual of Procedures 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
RADAR 
Response Adjusted for Days of Antibiotic Risk 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDCC 
Statistical and Data Coordinating Center 
 
 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
US 
United States 
USP 
United States Pharmacopeia 


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PROTOCOL SUMMARY 
Title: 
A Phase IV Double-Blind, Placebo-Controlled, Randomized Trial 
to Evaluate Short Course vs. Standard Course Outpatient 
Therapy of Community Acquired Pneumonia in Children 
(SCOUT-CAP) 
Phase: 
IV 
Population: 
Approximately 400 subjects aged 6-71 months of age with 
community acquired pneumonia (CAP) 
Description of 
Sites/Facilities Enrolling 
Participants: 
5 to 10 US outpatient sites 
Study Duration: 
25 months 
Subject Participation 
Duration: 
~1 month after beginning antibiotic therapy 
Description of Agent or 
Intervention: 
Oral suspensions of amoxicillin, amoxicillin-clavulanate, cefdinir 
and matching placebos 
Objectives: 
 
 
Primary: 
1. To compare the composite overall outcome (Desirability 
of Outcome Ranking, DOOR) among children 6-71 
months of age with CAP assigned to a strategy of short 
course (5 days) vs. standard course (10 days) outpatient 
beta-lactam therapy at Outcome Assessment Visit #1 
(Study Day 8 +/- 2 days) 
 
Secondary: 
1. To compare the composite overall outcome (DOOR) 
among children 6-71 months of age with CAP assigned 
to a strategy of short course (5 days) vs standard course 
(10 days) outpatient beta-lactam therapy at Outcome 
Assessment Visit #2 (Study Day 22 +/- 3 days) 
2. To compare the resolution of symptoms (a component of 
DOOR) among children 6-71 months of age with CAP 
assigned to a strategy of short course (5 days) vs 
standard course (10 days) outpatient beta-lactam 
therapy at Outcome Assessment Visits #1 and #2 


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3. To compare the clinical response (a component of 
DOOR) among children 6-71 months of age with CAP 
assigned to a strategy of short course (5 days) vs 
standard course (10 days) outpatient beta-lactam 
therapy at Outcome Assessment Visits #1 and #2 
4. To compare solicited events (a component of DOOR) 
among children 6-71 months of age with CAP assigned 
to a strategy of short course (5 days) vs standard course 
(10 days) outpatient beta-lactam therapy at Outcome 
Assessment Visits #1 and #2  
5. To compare medically attended visits to Emergency 
Departments (ED) or outpatient clinics, hospitalizations, 
surgical procedures, and receipt of non-study systemic 
antibiotics (components of the clinical response) among 
children 6-71 months of age with CAP assigned to a 
strategy of short course (5 days) vs standard course (10 
days) outpatient beta-lactam therapy at Outcome 
Assessment Visits #1 and #2  
 
Exploratory: 
1. To examine the robustness of results of DOOR 
comparisons when increasing the threshold in assigning 
different ranks due to differing numbers of days of 
antibiotic use from a one day difference to a two, three, 
four, or five day difference. 
 
Description of Study 
Design: 
Double-Blind, Placebo-Controlled, Randomized Trial 
Estimated Time to 
Complete Enrollment: 
Approximately 24 months 
 
Figure 1:Study Schematic 


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1 
KEY ROLES 
Individuals: 
Principal Investigator 
 
C. Buddy Creech, MD, MPH 
Associate Professor of Pediatrics, Division of Pediatric Infectious 
Diseases 
Director, Vanderbilt Vaccine Research Program 
CCC-5319 Medical Center North 
1161 21st Avenue South 
Nashville, TN 37232 
Phone: 615-343-0332 
Email: buddy.creech@vanderbilt.edu 
 
 
Antibiotic Resistance Leadership Group (ARLG) Protocol 
Co-Principal Investigators 
W. Charles Huskins, MD, MSc  
Mayo Clinic  
200 First Street SW  
Rochester, MN 55905 
Phone: 507-255-8464  
Email: huskins.charles@mayo.edu 
 
 
Theoklis Zaoutis, MD, MSCE 
The Children's Hospital of Philadelphia,  
34th and Civic Center Boulevard,  
CHOP North, Room 1527,  
Philadelphia, PA 19104 
Phone: (267) 426-5570 
Email: zaoutis@email.chop.edu 
 
National Institutes of Health 
DMID Medical Monitor 
Venus Shahamatdar, MD 
DMID/NIAID/NIH/HHS 
5601 Fishers Lane, 7E54 
Rockville, MD 20852 
Phone: (240) 627-3369 
Email: shahamav@mail.nih.gov 
 
 
Statistical and Data 
Coordinating Center: 
 
The Emmes Corporation  
401 N. Washington St. Suite 700 
Rockville, MD  20850 
Phone: 301-251-1161 
Email: arlg_studies@emmes.com  
 
 


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Safety and 
Pharmacovigilance 
Contractor: 
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support  
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20814 
SAE Hot Line: 1-800-537-9979 (US) 
SAE Fax: 800-275-7619 (US) 
SAE Email: PVG@dmidcroms.com 
 
 
Clinical Materials 
Services 
Fisher BioServices 
c/o DMID Clinical Materials Services 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350 
Fax: 240-477-1360 
Email: DMID.CMS@ThermoFisher.com 
 
 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
The World Health Organization estimates 156 million cases of pneumonia occur annually in 
children <5 years of age.1 In the United States (US), an estimated 1.5 million ambulatory visits 
for community-acquired pneumonia (CAP) in children occur annually.2 Hospitalizations for CAP 
in children have decreased after the introduction of pneumococcal conjugate vaccine.3 Further, 
in a pneumonia etiology study of >2500 children hospitalized with CAP in 3 US cities between 
2010 and 2012, viral pathogens accounted for >70% of detections, while bacteria were 
identified in <20%.4 However, ambulatory visits have not decreased, and pediatric CAP remains 
a very common infection for which antibiotics are generally prescribed.2 
 
A 2011 Infectious Diseases Society of America (IDSA) guideline for management of CAP in 
children provides recommendations for antibiotic therapy.5 Regarding the treatment duration for 
beta-lactam antibiotics, the guideline states “courses of 10 days have been best studied.” Two 
studies conducted in resource-poor settings found no difference in outcomes between 3 vs. 5 
days of oral therapy or 3 days of oral therapy vs. placebo for non-severe pneumonia.6,7 
However, these studies likely included many subjects with viral infection because substantial 
proportions had no radiographic findings or included children with wheezing. While stating 
“shorter courses may be just as effective,” the IDSA guideline concluded there was insufficient 
evidence to recommend short course therapy.5 The guideline identified clinical trials that provide 
information on the “shortest duration of therapy to decrease the development of antimicrobial 
resistance and the risk of antimicrobial toxicity” as a priority for future research.5 
 
2.2 
Rationale 
 
In 2014, a randomized trial of short vs. standard course therapy in young children in Israel with 
CAP suspected to be of bacterial origin found a higher rate of treatment failure (40%) in subjects 
treated for only 3 days vs. subjects treated for 5 or 10 days.8 The study was underpowered to 
detect a difference in treatment failure between subjects treated for 5 vs. 10 days, but treatment 
failure did not occur in either group.  
 
The proposed study will test the effectiveness of short (5-day) vs. standard (10-day) course 
therapy in children who are diagnosed with CAP and initially treated in outpatient clinics, urgent 
care facilities, and emergency departments. The study will specifically address whether short 
course therapy is superior to standard therapy among children that have clinically improved 
since diagnosis. If superior to standard course therapy, short course therapy could reduce 
antibiotic exposure among young children. We will use a study methodology similar to the 
SCOUT Study (“Short Course Therapy for Urinary Tract Infections in Children”)—a randomized, 
double-blind, placebo-controlled non-inferiority trial of short course antimicrobial therapy for 
urinary tract infection in children sponsored by NIAID through the “Targeted Clinical Trials to 
Reduce the Risk of Antimicrobial Resistance” initiative.  However, the SCOUT-CAP trial will use 
a superiority study design using an ordinal composite overall outcome (Desirability of Outcome 
Ranking, DOOR, see 3.2.1 Primary Outcome Measures)—to test the hypothesis that short 


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course (5 day) therapy is superior to standard course (10-day) beta-lactam therapy in children 
who have experienced early clinical improvement of pneumonia. 
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
The potential risk of short course therapy is that clinical outcomes may not be equivalent to 
standard course therapy.  Specifically, the percent of children with adequate clinical response 
(or in this case, no relapse of illness) may be lower in children receiving short course therapy.  
Adequate clinical response can be defined as resolution or substantial improvement in clinical 
signs and symptoms (e.g., fever, cough, respiratory rate, work of breathing) and the lack of 
need for additional antibiotic therapy, additional contacts with the health care system, or surgical 
procedures for worsening pneumonia. The magnitude of this risk is not well established, 
although a study from Israel suggests it is small8; nevertheless, this degree of risk will be 
evaluated during this trial.  
2.3.2 Known Potential Benefits 
If, as assessed by the primary outcome, short course therapy is superior to standard course 
therapy, short course therapy will reduce antibiotic exposure among children with CAP. The 
potential benefits of reduced antimicrobial exposure involve benefits both to the individual child 
and the population as a whole.   
Potential benefits to the individual child include a simpler course of therapy, a lower risk of an 
adverse event associated with antibiotic therapy (e.g., antibiotic associated diarrhea, 
Clostridium difficile infection) and a lower risk of becoming colonized with antibiotic resistant 
bacteria.   
Potential benefits to the population include a lower prevalence of colonization with pathogenic 
antibiotic resistant bacteria among children treated for CAP.  Since these bacteria are 
transmissible, a lower prevalence of colonization among children treated for CAP confers a 
potential lower risk of colonization among all persons in the population, including children and 
adults regardless of whether they are treated with antibiotics.  
 


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3 
OBJECTIVES 
3.1 
Study Objectives 
 
Primary: 
1. To compare the composite overall outcome (Desirability of Outcome Ranking, DOOR) 
among children 6-71 months of age with CAP assigned to a strategy of short course (5 
days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome 
Assessment Visit #1 (Study Day 8 +/- 2 days) 
 
 
Secondary: 
1. To compare the composite overall outcome (DOOR) among children 6-71 months of age 
with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) 
outpatient beta-lactam therapy at Outcome Assessment Visit #2 (Study Day 22 +/- 3 
days) 
2. To compare the resolution of symptoms (a component of DOOR) among children 6-71 
months of age with CAP assigned to a strategy of short course (5 days) vs standard 
course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and 
#2 
3. To compare the clinical response (a component of DOOR) among children 6-71 months 
of age with CAP assigned to a strategy of short course (5 days) vs standard course (10 
days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2 
4. To compare solicited events (a component of DOOR) among children 6-71 months of 
age with CAP assigned to a strategy of short course (5 days) vs standard course (10 
days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2 
5. To compare medically attended visits to Emergency Departments (ED) or outpatient 
clinics, hospitalizations, surgical procedures, and receipt of non-study systemic 
antibiotics (components of the clinical response) among children 6-71 months of age 
with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) 
outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2 
Exploratory: 
1. To examine the robustness of results of DOOR comparisons when increasing the 
threshold in assigning different ranks due to differing numbers of days of antibiotic use 
from a one day difference to a two, three, four, or five day difference. 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
 
The primary endpoint/outcome measure is the DOOR at Outcome Assessment Visit #1. 
 
DOOR is defined as follows:  


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I. 
Each subject is evaluated according to the ordinal composite outcome (See Table 1 
below) and assigned an outcome rank ranging from 1-8. 
II. 
Desirability of Outcome Ranking (DOOR) is then assigned according to two rules: 
(i) When comparing two subjects with different ordinal responses, the subject with a 
better ordinal response receives a higher rank. 
(ii) When comparing two subjects with identical ordinal responses, the subject with 
fewer days of antibiotic use receives a higher rank. 
 
The ordinal composite outcome involves an assessment of whether the subject has an adequate 
clinical response and whether they have experienced any solicited events as defined below. 
 
 
Table 1. Ordinal Outcome 
 
Adequate clinical response1  
(Assessed at Outcome Assessment Visits 
#1 and #2) 
Solicited events3 
(Assessed at Outcome Assessment Visits 
#1 and #2) 
1 
Yes, with resolution of symptoms2 
None 
2 
Yes, with resolution of symptoms2 
Mild (Grade 1) 
3 
Yes, with resolution of symptoms2 
Moderate (Grade 2) 
4 
Yes, with resolution of symptoms2 
Severe (Grade 3) 
5 
Yes, with persistent symptoms of fever, 
tachypnea, or cough 
None or any grade 
6 
No, with ED/clinic visit but no hospitalization 
None or any grade 
7 
No, with hospitalization 
None or any grade 
8 
Death from any cause 
1Adequate clinical response is defined as the absence of a medically attended visit to an ED or 
outpatient clinic or hospitalization for persistent or worsening pneumonia that occurs after 
randomization and receipt of at least one dose of study drug. 
• 
Persistent or worsening pneumonia is defined as receipt of a non-study systemic 
antibiotic for pneumonia or treatment for a complication of pneumonia, including drainage 
of pleural fluid, placement of a chest tube, video assisted thoracoscopic surgery, or 
thoracotomy procedures.   
• 
Note: Receipt of a non-study antibiotic will not be regarded as satisfying this definition if it 
is related to a new diagnosis that is unrelated to the prior diagnosis of pneumonia. 
 
2Resolution of symptoms is defined as the absence of all of the following:  
• 
Oral, rectal, axillary, or tympanic temperature ≥38.3˚C (100.9˚F), confirmed by repeat 
measurement after at least 15 minutes, in the 24 hours preceding the Outcome 
Assessment Visit or measured at the Outcome Assessment Visit, unless attributed to a 
new process that is unrelated to the prior diagnosis of pneumonia; 
• 
Elevated respiratory rate (RR >50 breaths/minute for children <24 months of age and >40 
breaths/minute for children 24-71 months of age) at the time of the Outcome Assessment 
Visit; 
• 
Presence of cough grade 2 or 3 at the Outcome Assessment Visit, (defined in Table 2). 
 
3Solicited events (Table 3) will be captured daily until Outcome Assessment Visit #2; thereafter, 
parents/legal guardians will report symptoms based on memory aid and medical interview by 


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study staff. For those with multiple solicited events, the ordinal response table will be based 
upon the most severe solicited event. 
 
 
Table 2: Severity of Cough 
Symptom 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Cough 
Occasional coughing 
(less than 4 times 
hourly) 
Frequent coughing (4 or 
more times an hour], 
interferes with sleep) 
Almost constant coughing 
(never free of cough), makes 
sleep nearly impossible 
 
Table 3. Solicited Events Grading 
Symptom 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Irritability 
More irritable or fussy 
than usual but can be 
consoled; no interference 
with smiling/playing 
Irritability or fussiness that 
is difficult to console and 
interferes with smiling and 
playing 
Irritability or fussiness that 
lasts for more than 4 
consecutive hours in a 24 
hour period or cannot be 
consoled 
Vomiting  
1 episode/day  
2-3 episodes/day  
≥4 episodes/day  
Diarrhea  
Looser than normal stools 
occurring 3-6 times/day 
Looser than normal stools 
occurring >6 times/day  
Bloody diarrhea, or diarrhea 
that requires medical 
intervention, laboratory 
testing, or hospitalization 
Allergic 
Reaction 
Localized rash or  
pruritus without rash 
Diffuse rash 
(maculopapular or 
urticarial)  
Generalized rash consistent 
with Stevens-Johnson 
Syndrome, erythema 
multiforme, or toxic 
epidermal necrolysis; 
anaphylaxis; or  
angioedema  
Stomatitis 
Oral lesions associated 
with parenteral report of 
mild oral discomfort  
Oral lesions associated with 
difficulty swallowing, but 
able to eat and drink 
Oral lesions associated with 
inability to swallow solids or 
liquids; requires medical 
intervention, IV fluids, or 
hospitalization 
Candidiasis 
Mild mucocutaneous 
candidiasis or diaper 
dermatitis, with no 
treatment or topical 
treatment only 
Moderate mucocutaneous 
candidiasis requiring oral 
antimicrobial treatment 
Severe mucocutaneous 
candidiasis; requires medical 
intervention, intravenous 
treatment, or hospitalization 
 
3.2.2 Secondary Outcome Measures 
Secondary outcome measures include: 
1. DOOR at Outcome Assessment Visit #2. 
2. Resolution of symptoms (a component of DOOR) at each outcome assessment visit, 
defined as the absence of fever, tachypnea, or cough of grade 2 or higher. 


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3. Adequate clinical response rates (a component of DOOR) at each outcome assessment 
visit, defined as the absence of a medically attended visit to an ED or outpatient clinic or 
hospitalization for persistent or worsening pneumonia that occurs after randomization and 
receipt of at least one dose of study drug. 
4. Frequency of solicited events at each outcome assessment visit, as listed in Table 3.  
5. Medically attended visits to ED or clinic; hospitalizations; surgical procedures; and receipt 
of non-study systemic antibiotics for persistent or worsening pneumonia (as defined 
above) at each outcome assessment visit 
i. 
Individual event types (e.g., medical visits, hospitalizations, surgical procedures, 
and receipt of non-study systemic antibiotics) will be compared between treatment 
groups. 
6. Medically attended visits to ED or clinic; hospitalizations; surgical procedures; and receipt 
of non-study systemic antibiotics for all causes at each outcome assessment visit  
i. 
Individual event types (e.g., medical visits, hospitalizations, surgical procedures, 
and receipt of non-study systemic antibiotic) will be compared between treatment 
groups. 
3.2.3 Exploratory Outcome Measures 
 
1. DOOR at Outcome Assessment Visits #1 and #2, when increasing the threshold in 
assigning different ranks due to differing numbers of days of antibiotic use from a one 
day difference to a two, three, four, or five day difference.  
 


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4 
STUDY DESIGN 
This is a multi-center, randomized, double-blind, placebo-controlled, superiority clinical trial 
evaluating short course (5 day) vs. standard course (10 day) of oral beta-lactam antibiotic 
therapy (amoxicillin, amoxicillin-clavulanate, cefdinir) for treatment of CAP in children 6-71 
months of age who have clinically improved prior to enrollment. The study will randomize 
approximately 400 enrolled subjects to one of the two study arms (approximately 200 children in 
each arm) in order to reach 360 subjects completing Outcome Assessment Visit 1. Subjects will 
be randomized (1:1) to receive either a standard course of the initially prescribed antibiotic (10 
days) or a short course of the initially prescribed antibiotic (5 days) plus 5 days of matching 
placebo.   
 
The study will recruit potential subjects from children who are diagnosed with CAP and who are 
initiated on oral beta-lactam therapy (amoxicillin, amoxicillin-clavulanate, cefdinir) by healthcare 
providers in EDs, outpatient clinics, and urgent care centers at the study sites. Day -5 is defined 
as the date on which oral beta-lactam therapy is initiated for a diagnosis of CAP.  Potential 
subjects will be identified at any time following clinical diagnosis of pneumonia. These subjects 
will be assessed for eligibility and enrolled on Day -3 to -1 of their initially prescribed oral beta-
lactam therapy.  Subjects may also be enrolled on Day 1 (the first day of receipt of study agent) 
provided they have not yet received any doses of the healthcare provider-prescribed antibiotic 
therapy for that day.  
 
A Schedule of Events is provided in Appendix A.  
 
Visit 1:  Enrollment Visit. Subjects who meet the eligibility criteria, and whose parent/guardian 
consents for participation in the study, will complete an Enrollment Visit on Day -3 to -1. 
Subjects satisfying the inclusion criteria with no exclusion criteria will be enrolled and 
randomized. Enrolled subjects will continue to receive the initially prescribed antibiotic through 
Day -1.  The subjects’ parents/guardians will be instructed to contact study personnel if their 
child develops fever or worsening respiratory symptoms (worsening cough, increased work of 
breathing, any other concerning symptoms in the parents’ estimation) following enrollment.  
 
Randomization:  Enrolled subjects will be randomized to short vs. standard course therapy at a 
1:1 ratio, with stratification by 1) age group (<24 months vs. 24-71 months), 2) initially 
prescribed antibiotic (amoxicillin vs. amoxicillin-clavulanate vs. cefdinir), and 3) treatment site 
(emergency department vs. outpatient clinic/urgent care facility). 
 
Intervention:  Subjects will continue on the initially prescribed antibiotic through Day -1, until 
they have completed 5 days (i.e., 5 scheduled doses of once daily medication, 10 scheduled 
doses of twice daily medication) of antibiotic therapy [e.g., if a subject takes the first dose of 
antibiotic in the afternoon of Day -5, the first dose of study agent would occur on the afternoon 
of Day 1, providing 10 total scheduled doses of a twice daily prescribed antimicrobial]. The first 
day of receipt of study agent will be Day 1.  Subjects assigned to standard course therapy will 
receive 5 additional days (10 doses) of the same initially prescribed antibiotic, with standardized 
twice-daily dosing.  Subjects assigned to short course therapy will receive 5 more days (10 
doses) of a matching placebo.  Both the study agent and placebo may appear different than the 
commercial formulation the child originally received. The placebo will appear indistinguishable in 


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color, taste, thickness, and consistency as the active antibiotic the child would otherwise receive 
in the study. The study product will be labeled with a numerical code that masks site 
investigators, site staff, parent(s)/guardian(s) and children to the formulation. 
 
Follow-up and Assessment of Endpoints:  Subjects will be scheduled for the following 
assessment visits: 
 
Visit 2: Outcome Assessment Visit #1, Day 6 to 10 (1-5 days after completing the study agent). 
Subjects will be evaluated for the components of the composite overall outcome, which include 
the adequacy of the subject’s clinical response; persistence of symptoms of fever, tachypnea, or 
cough; the occurrence of any solicited events; and the duration of antibiotic therapy (both study 
product/placebo and any additional oral or parenteral antibiotic therapy prescribed by study or 
non-study providers). 
 
Visit 3: Outcome Assessment Visit #2, Day 19 to 25 (14-20 days after completing the study 
agent). Subjects will be evaluated for the components of the composite overall outcome, which 
include the adequacy of the subject’s clinical response; persistence of symptoms of fever, 
tachypnea, or cough; the occurrence of any solicited events; and the duration of antibiotic 
therapy (both study product/placebo and any additional oral or parenteral antibiotic therapy 
prescribed by study or non-study providers). 
 
Subjects who are identified as having an inadequate clinical response prior to Outcome 
Assessment Visit #1 will be asked to complete Outcome Assessment Visits #1 and #2 in order 
to evaluate the occurrence of any solicited events and the duration of antibiotic therapy (both 
study product/placebo and any additional oral or parenteral antibiotic therapy prescribed by 
study or non-study providers).  
 
Subjects will be invited to contribute oropharyngeal and stool specimens at specified times 
throughout the study for future use (see Appendix A, Schedule of Events). Additional informed 
consent will be obtained for future use sample collection. 
 
 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Subjects who are diagnosed with CAP in EDs, urgent care facilities, and clinics will be screened 
for eligibility.  Screening will continue until 400 subjects are enrolled cumulatively across all the 
study sites.  The study will recruit potential subjects from children who are diagnosed with CAP 
and who are initiated on antibiotic therapy using oral beta-lactam therapy (amoxicillin, 
amoxicillin-clavulanate, cefdinir) by healthcare providers in EDs, outpatient clinics, and urgent 
care centers at the study sites. Potential subjects will be identified at any time following clinical 
diagnosis of pneumonia. Other forms and/or mechanisms of recruitment may also be used. The 
local IRB will approve recruitment materials prior to use. 
Subject Inclusion and Exclusion Criteria must be confirmed by a study clinician licensed to make 
medical diagnoses.  
No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Questions about eligibility will be directed toward the DMID Medical Officer. 
5.1 
Subject Inclusion Criteria 
Eligible subjects may be included in the study if they meet ALL of the following criteria at 
the Enrollment Visit (Day -3 to -1): 
1. Age 6 – 71 months 
2. Provider diagnosis of CAP and prescription of antibiotic therapy with amoxicillin1, 
amoxicillin-clavulanate1, or cefdinir2 
1 amoxicillin or amoxicillin-clavulanate prescribed at a minimum amoxicillin dose 
of 60 mg/kg/day 
2 cefdinir prescribed at a minimum dose of 10 mg/kg/day 
3. Parental report of clinical improvement3 
3 based on lack of either subjective or known fever (temperature ≥38.3°C in the 
preceding 24 hours); current respiratory rate no greater than 50 breaths/minute 
(<2 years of age) or 40 breaths/minute (> 2 years of age); and current grade of 
cough <3.  
4. Ability of a parent or guardian to understand and comply with the study 
procedures and be available for all study visits 
5. Signed written informed consent by a parent or guardian 
5.2 
Subject Exclusion Criteria 
Subjects will be excluded from the study if they meet ANY of the following criteria: 
1. Treatment with any systemic antibiotic therapy within 7 days before the diagnosis 
of CAP 


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2. Initial therapy for CAP with combination antibiotic therapy4 
4 amoxicillin, amoxicillin/clavulanate or cefdinir plus one or more additional oral, 
intravenous, or intramuscular antibiotics 
3. History of anaphylaxis or severe drug allergy to amoxicillin, if prescribed 
amoxicillin or amoxicillin/clavulanic acid; or oral cephalosporin antibiotics (except 
cefaclor), if prescribed cefdinir 
4. Presence of concomitant bacterial infection that requires >5 days of antibiotic 
therapy 
5. Radiographic findings (where applicable) of complicated pneumonia5  at 
presentation or any subsequent chest radiograph up to the time of enrollment 
5 Clinically significant pleural effusion, lung abscess, or pneumatocele 
6. Hospitalization6 for pneumonia during Day -5 to -1 of antibiotic therapy for CAP 
6Subjects who require serial clinical assessments, but are discharged within 24 
hours will not be considered hospitalized and will not satisfy this exclusion 
criterion.  
7. Pneumonia due to S. aureus or group A streptococcus documented by positive 
blood culture or PCR, at the time of enrollment. 
8. History of pneumonia within the previous 6 months  
9. History of persistent asthma7 within the previous 6 months or current acute 
asthma exacerbation8 
7 Persistent asthma is defined as receiving daily asthma maintenance therapy 
such as inhaled corticosteroids, cromolyn, theophylline, or leukotriene receptor 
antagonists.  
8 Acute asthma exacerbation is defined as receiving concomitant bronchodilator 
therapy and systemic corticosteroids. 
10. Provider-diagnosis of aspiration pneumonia, bronchiolitis, or bronchitis.  
11. Surgery or other invasive procedures of the upper or lower airway (e.g., 
bronchoscopy, laryngoscopy) with general anesthesia or hospitalization ≤7 days 
before diagnosis of CAP 
12. History of an underlying chronic medical condition9  
9 including chronic heart disease, chronic lung disease (except asthma),congenital anomalies of 
the airways or lung, cystic fibrosis, chronic renal disease including nephrotic syndrome, protein-
losing enteropathy of any cause, severe malnutrition, neurocognitive disorders, metabolic 
disorders (including phenylketonuria), or genetic disorders (note: genetic syndromes such as 
Down syndrome and Edwards Syndrome are excluded; however, children with genetic disorders 
(e.g., hemophilia) but who do not have a genetic syndrome may not satisfy this particular 
exclusion criterion; it is important that children with such genetic disorders do not have 
symptoms and/or comorbidities that would pose additional risk to them nor jeopardize the 
adequacy of study assessments.”) 


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13. History of a condition that compromises the immune system10  
10 HIV infection, primary immunodeficiency, anatomic or functional asplenia; 
receipt of a hematopoietic stem cell or solid organ transplant at any time; receipt 
of immunosuppressive therapy including chemotherapeutic agents, biologic 
agents, antimetabolites or radiation therapy during the past 12 months; or daily 
use of systemic corticosteroids for more than 7 consecutive days during the past 
14 days. 
14. Any other condition that in the judgment of the investigator precludes 
participation because it could affect the safety of the subject 
15. Current enrollment in another clinical trial of an investigational agent 
16. Previous enrollment in this trial  
5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
 
Per International Conference on Harmonisation (ICH) guideline E6: Good Clinical Practice 
(GCP), screening records will be kept at each participating site to document the reason why an 
individual was screened, but failed trial entry criteria.  The reasons why individuals failed 
screening will be recorded on screening logs maintained by each site.  
 
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled.  Subjects will be assigned to either placebo or active study drug (the 
same antibiotic that they were prescribed for the first 5 days of treatment). After a subject is 
enrolled, they will be given a random treatment assignment of study product to either short 
course or standard course therapy. Randomization to short vs. standard course therapy will be 
at a 1:1 ratio (approximately 200 subjects per treatment group). Subjects will be stratified by age 
group <24 months vs. 24-71 months), type of initial antimicrobial therapy, and initial treatment in 
an ED or outpatient clinic/urgent care center. 
 
Enrollment of subjects will be performed online using AdvantageEDC.  The list of randomized 
treatment assignments will be prepared by statisticians at The Emmes Corporation and included 
in The Emmes Corporation’s Internet Data Entry System (IDES). IDES will assign each 
volunteer a treatment code from the list after the necessary data have been entered into the 
system. A designated individual at each site will be provided with a treatment key, which links 
the treatment code to the actual treatment assignment, which will be kept in a secure place. 
 
Instructions for subject enrollment are included in the Manual of Procedures (MOP). Manual 
back-up randomization procedures are provided in the MOP for use in the event that the site 
temporarily loses access to the Internet or the online enrollment system is unavailable. 
5.3.2 Masking Procedures 
This is a double-blind clinical trial. The study subjects and their parents/guardians, investigators, 
and study team staff will remain blinded to study treatment assignment throughout the study. 
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the three antibiotics (amoxicillin, amoxicillin-clavulanate, cefdinir) the subject was initially 
prescribed.  
 
The study products and placebo will be prepared by the unblinded site Research Pharmacist. 
Only the preparing pharmacist will be aware of the study product bottle assignments. For 
subjects randomized to standard course therapy, the pharmacy will provide the same 
medication prescribed initially. For subjects randomized to short course therapy, the pharmacy 
will provide a placebo that resembles the appearance (color and texture), flavor, and 
consistency of the active study product. All study products will be packaged with an identical 
appearance.  Additional details regarding dispensing procedures will be included in the protocol-
specific MOP.  
 
The study product will be labeled with a numerical code that masks site investigators, site staff, 
parent(s)/guardian(s) and children to the formulation. The unblinded site Research Pharmacist 
will be the only person to perform the unmasking if needed.  Additional details regarding labeling 
procedures will be included in the protocol-specific MOP. 
 
During the consenting process it will be explained to the parents of any potential subjects that 
the study product (treatment or placebo) that will be provided for administration after Day 5, may 
or may not taste exactly the same as the originally prescribed medication, and that the look and 
smell may be slightly different because it might be supplied by a different manufacturer than that 
of the initially prescribed antibiotic. Parents will also be instructed that the amount or frequency 
of the prescribed study product has been made uniform across all study groups; therefore, the 
amount/frequency may be different than originally prescribed by their provider (e.g., receipt of 
once daily cefdinir is not excluded, but upon study entry, those subjects will receive either twice 
daily cefdinir or placebo).  
5.3.3 Reasons for Withdrawal 
 
Subject Withdrawal 
Subjects’ parents/guardians may voluntarily withdraw their consent for study participation at any 
time and for any reason, without penalty. 
 
A subject may withdraw or be withdrawn from the study for any of the following reasons: 
• 
Withdrawal of consent 
• 
Subject lost to follow-up 
• 
Termination of the study 
• 
Any new information becomes available that makes further participation unsafe. 
 
Subjects who wish to withdraw from further study participation will be asked to continue to 
participate in follow-up visits. At the time of withdrawal, subjects will undergo an early termination 
visit, if they are not willing to participate in the remaining follow-up visits. 
 
Discontinuation of Treatment 
A subject may be discontinued from treatment and continue to be followed if any of individual 
halting rules, as defined in Section 9.5.2, are met. 


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5.3.4 Handling of Withdrawals  
 
The primary reason for withdrawal from the study will be recorded on the Study Status data 
collection form.  Parents/guardians will be encouraged to complete the Early Termination Visit, 
as listed in Section 7.5.  Unless they expressly state that they wish to have no additional follow-
up or data collection, subjects who withdraw from the study will receive a follow-up phone call 
approximately one week after their withdrawal.  This will allow the site to assess the status of 
the subject and determine if any medical follow up care was sought.  Although subjects are free 
to withdraw at any time or may be withdrawn by the site PI or appropriate sub-investigator at 
any time, subjects will be encouraged to remain in this study for follow-up assessments (may be 
by telephone rather than in person) continuing through approximately 1 month after study 
treatment.  
 
Every attempt will be made to follow all ongoing solicited events or serious adverse events, as 
well as new-onset chronic medical conditions, to resolution or until the subject’s condition 
becomes stable. 
  
Subjects who discontinue treatment will be followed according to the study protocol and will not 
be replaced.   
5.3.5 Termination of Study  
 
The National Institute of Allergy and Infectious Diseases (NIAID), the IRB of record, or the FDA 
may discontinue the study at any time. Should the study be discontinued prior to completion, 
any subjects on study will complete study visits, if medically appropriate but no new subjects 
would be enrolled.   
 
Although the study Sponsor has every intention of completing this study, it reserves the right to 
terminate this study at any time for clinical or administrative reasons. Reasons for termination 
include, but are not limited to, study closure due to DSMB review and recommendation and at 
the discretion of DMID. 
 


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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
 
Amoxicillin 
Amoxicillin, USP is a semisynthetic antibiotic, an analog of ampicillin, with a broad spectrum of 
bactericidal activity against many gram-positive and gram-negative microorganisms.  Amoxicillin 
is similar to penicillin in its bactericidal action against susceptible bacteria during the stage of 
active multiplication. It acts through the inhibition of cell wall biosynthesis that leads to the death 
of the bacteria. 
 
Amoxicillin-Clavulanate 
Amoxicillin-Clavulanate is an oral antibacterial combination consisting of semisynthetic antibiotic 
amoxicillin and the beta-lactamase inhibitor, clavulanate potassium.  Clavulanic acid is 
particularly active against the clinically important plasmid-mediated beta-lactamases frequently 
responsible for transferred drug resistance to penicillins and cephalosporins. 
 
Cefdinir 
Cefdinir is an extended-spectrum, semisynthetic cephalosporin.  Bactericidal activity of cefdinir 
results from inhibition of cell wall synthesis and is stable in the presence of some, but not all, 
beta-lactamase enzymes. As a result, many organisms resistant to penicillins and some 
cephalosporins are susceptible to cefdinir. 
6.1.1 Acquisition 
Amoxicillin, Amoxicillin-Clavulanate, and Cefdinir will be obtained by the DMID Clinical Materials 
Services (CMS, Fisher BioServices).  The matching placebo for each active drug will be will be 
prepared by a compounding pharmacy and stored at the DMID CMS.  
 
The compounding, filling, packaging and labeling of study drug placebos will be done according 
to applicable regulatory requirements.  All active study drugs and placebos will be acquired 
through the DMID CMS. 
 
Study product (amoxicillin, amoxicillin-clavulanate, cefdinir and matching placebos) will be 
shipped from the DMID CMS to the study site upon request and approval by DMID. 
6.1.2 Formulation, Packaging, and Labeling 
6.1.2.1 
Amoxicillin 
Amoxicillin will be supplied as an oral powder for suspension in the following strength:  400mg/ 
5mL packaged in 100mL bottles.  The 400mg/5mL strength contains 400mg of amoxicillin as the 
trihydrate in each 5mL of reconstituted suspension. 
6.1.2.2 
Placebo for Amoxicillin 
 


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Placebo will be supplied as matching liquid.  In order to maintain the blind, the liquid placebo will 
be formulated for the same appearance (color and texture), flavor and consistency as the active 
study drug and will be provided in 100mL bottles. 
6.1.2.3 
Amoxicillin-Clavulanate 
Amoxicillin-clavulanate will be supplied as an oral powder for suspension in the following 
strength:  400mg/ 5mL packaged in 100mL bottles.    The 400mg/ 5mL strength contains 400mg 
of amoxicillin and 57mg of clavulanic acid as a potassium salt in each 5mL of reconstituted 
suspension.  Each 5mL of the 400mg/ 5mL strength contains 0.29mEq of potassium.  The 
400mg/ 5mL formulations contain aspartame and should not be used by phenylketonurics. 
6.1.2.4 
Placebo for Amoxicillin-Clavulanate 
Placebo will be supplied as matching liquid.  In order to maintain the blind, the liquid placebo will 
be formulated for the same appearance (color and texture), flavor and consistency as the active 
study drug and will be provided in 100mL bottles. 
6.1.2.5 
Cefdinir 
Cefdinir will be supplied as a white to off-white oral powder for suspension in the following 
strengths:  125mg/ 5mL and 250mg/ 5mL packaged in 100mL bottles.  The 125mg/ 5mL 
strength contains 125mg of cefdinir in each 5mL of reconstituted suspension.  The 250mg/ 5mL 
strength contains 250mg of cefdinir in each 5mL of reconstituted suspension.  Each 5mL of the 
250mg/ 5mL strength contains 1.37g of sucrose and each 5mL of the 125mg/5mL strength 
contains 1.5g of sucrose. Certain formulations from different manufacturers may contain up to 
2.86g of sucrose per 5mL.  
The lower strength (125mg/ 5mL) will be used in the lower weight bands (or as originally 
prescribed prior to enrollment) and the higher strength (250mg/ 5mL) will be used in the higher 
weight bands (or as originally prescribed prior to enrollment) as described in the protocol-
specific MOP. 
6.1.2.6 
Placebo for Cefdinir 
Placebo will be supplied as matching liquid for each of the active strengths provided.  In order to 
maintain the blind, the liquid placebo will be formulated for the same appearance (color and 
texture), flavor and consistency as the active study drug and will be provided in 100mL bottles.   
6.1.2.7 
Packaging and Labeling 
 
The active study drug will be supplied in their original manufacturer’s bottles.  The placebo 
supplied for each active study drug will be filled and packaged by the compounding pharmacy.  
Each container will also be labeled in compliance with applicable regulatory requirements, 
including the FDA-required cautionary statement “Caution- New drug -Limited by Federal (or 
United States) Law to Investigational Use Only.” As per Section 6.2.2, at the time of study 
product preparation, the site pharmacist will transfer the contents of the active and placebo into 
identical containers and affix with blinded labels for dispensing to the subject. 


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6.1.3 Product Storage and Stability 
6.1.3.1 
Amoxillin 
Store dry powder at 20˚C to 25˚C (68˚F to 77˚F) [See USP Controlled Room Temperature] for 
unreconstituted powder  
Upon reconstitution, when stored under refrigeration or room temperature, any remaining or 
unused portion must not be used after 14 days.  Refrigerated storage is preferred, but not 
required. 
6.1.3.2 
Placebo for Amoxicillin 
Store the suspension at 2°C to 8°C. 
To maintain the blind, upon dispensing, parents/caregivers will be given the same storage 
instructions as the active drug. 
6.1.3.3 
Amoxicillin-Clavulanate 
Store dry powder at 20˚C to 25˚C (68˚F to 77˚F) [See USP Controlled Room Temperature]. 
Upon reconstitution, the suspension must be stored under refrigeration and any remaining or 
unused portion must not be used after 10 days  
6.1.3.4 
Placebo for Amoxicillin-Clavulanate 
Store the suspension at 2°C to 8°C. 
To maintain the blind, upon dispensing, parents/caregivers will be given the same storage 
instructions as the active drug. 
6.1.3.5 
Cefdinir 
Store dry, unsuspended powder at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room 
Temperature]. 
Upon reconstitution, the suspension must be stored at room temperature and any remaining or 
unused portion must not be used after 10 days. 
6.1.3.6 
Placebo for Cefdinir 
Store the suspension at 2°C to 8°C. 
To maintain the blind, upon dispensing, parents/caregivers will be given the same storage 
instructions as the active drug. 


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6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product 
6.2.1 Dosage 
Subjects will complete five days of their originally prescribed antibiotic and then take 5 days of 
the study product, as follows: 
Amoxicillin and Amoxicillin-Clavulanate 
Amoxicillin and Amoxicillin-Clavulanate will be dosed based on the amoxicillin component as 
80-100 mg/kg/day (maximum 2000 mg/day) divided twice daily. 
The matching placebo will be dosed at the same volume calculated for the active dose. 
Cefdinir 
Cefdinir will be dosed as 12-16 mg/kg/day (maximum 600mg/ day) divided twice daily. 
The matching placebo will be dosed at the same volume calculated for the active dose. 
6.2.2 Preparation 
The site Research Pharmacist must be unblinded and will prepare the active and placebo study 
products for dispensing to the subject. 
Instructions for reconstitution of each active drug will be provided in the protocol-specific MOP.  
Upon reconstitution, active amoxicillin, amoxicillin-clavulanate, and cefdinir will be transferred 
from their original commercial containers into new containers strictly for blinding/masking 
purposes.  The matching placebo liquid will be transferred into identical containers to maintain 
the blind. 
Additional details regarding subsequent labeling, preparation of kits, and procedures for 
dispensing or administration of study product will be described in the protocol-specific MOP. 
6.2.3 Administration 
All active and placebo study products will be orally administered via oral dosing syringe or 
dosing cup. For older children in whom a dosing cup is preferred, parents will be instructed to 
measure the drug in the oral dosing syringe prior to transferring to the dosing cup.  
6.3 
Modification of Study Intervention/Investigational Product for a Participant 
No modifications of study product are planned at this time. If a subject experiences any 
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6.4 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
After receipt of the study product, the site Principal Investigator (PI) is responsible for 
distribution and disposition of these study products, and has ultimate responsibility for drug 
accountability. As this is a blinded study, the site PI will delegate this responsibility to the 
unblinded site pharmacist.  Study product records must be maintained and document logs of 
receipt, accountability, and storage temperature conditions. These study product accountability 
and dispensing logs must be maintained in the study file.  Upon completion of the study and 
after the final monitoring visit, unused study product will be retained until monitored and 
released for disposition as per the Sponsor. 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product  
The investigator will maintain records documenting all study products administered to each 
subject for the entire study period. Subjects will be asked to complete a memory aid and bring 
their study product containers. The memory aid will be used to record daily study medication 
taken, concomitant medications (e.g., pain medication),  temperature, solicited events, and 
presence of cough. The study coordinator/investigator will document any missed doses of study 
medication and provide counseling per study sites’ routine procedures to promote compliance 
with study medication. The information on the memory aid will be recorded on a source 
document, but the memory aid will not be collected from the subject.  If a subject’s memory aid 
is not available, study medication compliance will be obtained by parental interview. The study 
coordinator/investigator will record how study drug compliance information was obtained.  In 
addition, study product containers will be collected. Study product which has been dispensed 
and has been returned to the pharmacy should be documented in the study product 
accountability log and discarded as biohazardous waste. 
6.6 
Concomitant Medications/Treatments 
Administration of any medications, therapies, or vaccines including dose and frequency, will be 
recorded on the appropriate data collection form. Concomitant medications will include all 
current medications and medications taken within 30 days prior to signing the informed consent 
form through the last study visit or early termination. Prescription and over-the-counter drugs will 
be included, as well as herbals, vitamins, and supplements. 
Use of new medication should prompt evaluation for the presence of a new diagnosis of chronic 
medical disease or condition. 
Medications that might interfere with the evaluation of the study product or may compromise 
participant safety should not be used during the study. Medications in this category include the 
prohibited medications per the Subject Exclusion Criteria (see Section 5.2). In addition, the site 
principal investigator or appropriate sub-investigator may identify other medications that should 
not be used due to a risk to subject safety. 


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7 
STUDY SCHEDULE 
7.1 
Screening  
 
Each study site will determine the most efficient procedures to identify potentially eligible 
subjects from primary care clinics, urgent care centers, and emergency departments affiliated 
with the study clinical trial centers. Providers will be informed about the study and provided with 
site-specific SCOUT-CAP provider information pamphlets summarizing the study design and 
participant eligibility criteria. Providers may also be asked to alert their patients about their 
practice’s participation in the SCOUT-CAP study, instructing them that study personnel may 
contact them to discuss potential research opportunities.  
 
The identification of potentially eligible subjects will vary by site and practice setting and will 
include direct communication with providers, review of clinical intake logs, and electronic health 
record (EHR) alerts that automatically screen for new pneumonia cases from medical records.  
 
Once a potentially eligible subject with the diagnosis of CAP is identified, study staff will first 
contact the treating clinic to confirm willingness to have the patient participate in the study. For 
subjects deemed potentially eligible, study staff will attempt to contact the parent(s)/guardian(s) 
by telephone. If the parent(s)/guardian(s) are contacted successfully, the study staff may use 
the telephone contact guide (see MOP). Study staff will explain the study protocol and describe 
the inclusion/exclusion criteria. Study staff will answer any questions and concerns the 
parent(s)/guardian(s) may have. If the parent(s)/guardian(s) are interested in the study, study 
staff will schedule the Enrollment Visit on Day -3 to Day -1 of antibiotic therapy.  
 
Parents/caregivers of potential subjects who express interest in participation will be contacted 
again by study staff prior to the Enrollment Visit to confirm the appointment time and location 
and to assess the presence of ongoing symptoms such as fever, respiratory rate, and cough.  If 
fever, elevated respiratory rate, or Grade 3 cough are present, the visit may be rescheduled for 
a later day, but no later than before receipt of the first dose of their initially prescribed antibiotic 
on the sixth consecutive calendar day of treatment.  In all instances, the parent/guardian will be 
instructed to continue administration of original antibiotic as instructed by the treating clinician 
until the Enrollment Visit.  
7.2 
Enrollment/Baseline 
At the Enrollment Visit, study staff will obtain written informed consent from the 
parent(s)/guardian(s) for the primary study and request consent for collection of throat swabs 
and stool specimens for future use.  Declination to participate in collection of future use samples 
will not affect participation in the primary study. After the parent/guardian has had the 
opportunity to ask questions and has signed the informed consent document, the following 
activities will be performed by the study staff:  
• 
Eligibility criteria will be reviewed; 
• 
A complete medical history and sociodemographic data will be obtained by interview 
with the subject’s parent(s)/legal guardian; 


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• 
A physical assessment will be performed to determine general appearance, hydration 
status; vital signs, including temperature, heart rate,  and respiratory rate; an 
assessment of work of breathing; and presence of skin rash; additionally, if indicated by 
the physical assessment or medical history, a physical examination by a study clinician 
may occur; 
* Note: physical assessments may be performed by physicians, advanced practice 
nurses, physician assistants, or nurses.  
• 
An initial assessment of clinical response will be obtained to include report of subjective 
fever, maximum temperature in the past 24 hours (if taken), and an assessment of 
improved activity and appetite since initiating antibiotic therapy; 
• 
All concomitant medications taken within 30 days of signing the informed consent form 
will be recorded; 
• 
Subjects who meet eligibility criteria will be enrolled in AdvantageEDCSM and randomly 
assigned to one of two arms: standard course therapy (5 days of active medication) vs. 
short course therapy (5 days of matching placebo); 
• 
Study product will be dispensed and study staff will review the study product with the 
subject’s family and review the study product storage and dosing instructions; 
• 
Subjects will be provided with a memory aid and other study-related materials to record 
daily temperature, solicited events, concomitant medications, presence of cough, and 
daily dose administration. Parents will be instructed that any temperatures over 100.9˚F 
should be repeated 15 minutes later in the same manner as the initial temperature. 
Study staff will instruct the parent/guardian to complete the memory aid in order to 
document adherence and to bring the medication bottle with them to the Outcome 
Assessment Visit #1. Study staff will also review the memory aid used to assess specific, 
solicited events; 
• 
Collection of a throat swab specimen if contributing future use samples; 
• 
Dispense containers for collection of a stool specimen, if participating in future use 
portion of the study. 
Since the Enrollment Visit will occur during Day 3-5 of treatment (Day -3 to -1), the subject will 
be instructed to complete the originally prescribed medication through Day -1 (after receipt of 
the last dose of the originally prescribed medication on the fifth consecutive calendar day of 
treatment) and to start study product on Day 1.  
Parents will be educated at the time of their child’s enrollment in the study about prompt and 
adequate treatment for recurrence of symptoms or solicited events. The subject’s 
parent/guardian will be instructed to contact their primary care provider as soon as possible in 
the event of worsening respiratory status, recurrence of fever, or for other concerns. 
Parents/guardians will also be asked to contact study personnel in the event of clinical 
deterioration (i.e., medical visit or hospitalization for pneumonia) or for any severe solicited 
events.  


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Study personnel will be available at each site for urgent issues related to the study or for 
communication with primary care providers who may have questions about the study.  
Subjects who do not meet eligibility criteria or decline consent will be instructed to continue their 
initially prescribed antibiotic unless otherwise advised by their treating clinician. 
7.3 
Follow-up  
 
Visit 2: Outcome Assessment Visit #1, Day 6-10 
Subjects will be seen for a follow-up visit on Day 6-10.  Prior to this visit, study staff will, when 
possible, make a preliminary assessment of the clinical response using the electronic health 
record to determine whether any of the following events have occurred after randomization and 
anticipated receipt of at least one dose of study agent. 
• 
The subject had a medically attended visit to an ED, urgent care, or clinic; 
• 
The subject was hospitalized; 
• 
The subject received non-study, systemic antibiotic therapy; 
• 
The subject underwent drainage of pleural fluid, placement of a chest tube, or video 
assisted thoracoscopic surgery.   
At the follow-up visit, study staff will complete the following procedures: 
• 
Medical history to determine whether medically attended visits, receipt of non-study 
systemic antibiotics, or surgical procedures have occurred;  
• 
Assessment of adequate clinical improvement as indicated by a parental report of lack of 
rectal, tympanic, axillary or oral temperature ≥38.3°C or 100.9°F, normalization of 
respiratory rate for age (<50 breaths/minute for children <24 months of age and <40 
breaths/minute for children 24-71 months of age), and grading of cough. 
• 
Physical assessment to determine vital signs (temperature, pulse and respiratory rates) 
and physical assessment (general appearance, hydration status, work of breathing, 
presence of skin rash);  
• 
Review of the subject’s memory aid to assess and record any solicited events and 
concomitant medications; 
• 
Review of potential protocol-defined SAEs; 
• 
Review of memory aid to assess treatment compliance; 
• 
Collection of study product bottle for drug accountability, if available; 
• 
Collection of a throat swab and stool specimen (if available), if consented for future use 
samples. 
 
If the subject develops signs or symptoms of pneumonia (including fever, increased work of 
breathing, or increased/worsening cough) or develops a severe solicited event, the child will be 
referred to his/her primary care provider or local urgent care center/ED. Study staff will assist in 
facilitating the follow up appointment. The study staff will share all pertinent information related to 
the study with the primary physician. 


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7.4 
Final Study Visit 
 
Visit 3: Outcome Assessment Visit #2, Day 19-25 
Subjects will be seen for a follow-up visit on Day 19-25.  Prior to this visit, study staff will make a 
preliminary assessment of the clinical response using the electronic health record to determine 
whether any of the following events have occurred since the previous visit. 
• 
The subject had a medically attended visit to an ED, urgent care, or clinic; 
• 
The subject was hospitalized; 
• 
The subject received non-study, systemic antibiotic therapy; 
• 
The subject underwent drainage of pleural fluid, placement of a chest tube, or video 
assisted thoracoscopic surgery.   
At the follow-up visit, study staff will complete the following procedures: 
• 
Medical history to determine whether medically attended visits, receipt of non-study 
systemic antibiotics, or surgical procedures have occurred;  
• 
Assessment of adequate clinical improvement as indicated by a parental report of lack of 
rectal, tympanic, axillary, or oral temperature ≥38.3°C or 100.9°F for >24 hours, 
normalization of respiratory rate for age (<50 breaths/minute for children <24 months of 
age and <40 breaths/minute for children 24-71 months of age), and grading of cough. 
• 
Physical assessment to determine vital signs (temperature, pulse, and respiratory rate) 
and physical assessment (general appearance, hydration status, work of breathing, 
presence of skin rash);  
• 
Review of the subject’s memory aid to assess and record any solicited events and 
concomitant medications; 
• 
Review of potential protocol-defined SAEs 
• 
Review of memory aid assess treatment compliance (if not reviewed at Visit 2); 
• 
Collection of study product bottle for drug accountability, if not collected at Visit 2 and if 
available 
• 
Collection of a throat swab and stool specimen (if available), if consented for future use 
samples. 
 
If the subject develops signs or symptoms of pneumonia (including fever, increased work of 
breathing, or increased cough) or develops a severe solicited event, the child will be referred to 
his/her primary care provider or local urgent care center/ED. Study staff will assist in facilitating 
the follow up appointment. The study staff will share all pertinent information related to the study 
with the primary physician. 
7.5 
Early Termination Visit 
Subjects who are withdrawn from the study will be asked to complete an early termination visit. 
Procedures at the early termination visit will be identical to the outcome assessment visits 
except no throat swab or stool specimen (if consented to participate in the collection of future 
use samples) will be collected. Unless they expressly state that they wish to have no additional 


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follow-up or data collection, subjects who withdraw from the study will receive a follow-up phone 
call approximately one week after their withdrawal.  Study staff will review the memory aid and 
determine if any follow-up medical care was sought.  
If the subject presents with symptoms such as fever and/or elevated respiratory rate at the Early 
Termination visit, the study team will inform the subject’s PCP/pediatrician and will urge the 
parent(s) to follow-up with their primary provider. 


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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
A screening medical history will be obtained by interview of subject’s parents/caregivers during 
the prescreening telephone call and will be confirmed at the time of enrollment. Parent(s)/ 
guardian(s) will be queried regarding a history of significant medical disorders of the head, eyes, 
ears, nose, throat, mouth, cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, 
kidney, urologic system, nervous system, blood, lymph nodes, endocrine system, 
musculoskeletal system, skin, and genital/reproductive tract.  A history of any allergies, cancer, 
immunodeficiency, or other chronic medical conditions will be obtained.  At follow-up visits, an 
interim medical history will be obtained by interview of subjects noting any changes since the 
previous clinic visit or contact.  The interim medical history should include an assessment for 
new medical conditions. 
Medication history (concomitant medications) will include a review of all current medications and 
medications taken within 30 days prior to signing the informed consent form through the last 
study visit.  All medications will be reported in the eCRF.  Prescription and over-the-counter 
drugs will be included as well as herbals, vitamins and supplements. Use of new medication 
should prompt evaluation for the presence of a new diagnosis of an acute or chronic medical 
disease or condition.   
At the enrollment visit, a physical assessment to assess eligibility will occur, which will include 
vital signs (temperature, pulse and respiratory rates); hydration status; an assessment of work 
of breathing; and presence of skin rash. If indicated based on subject’s medical history or 
physical assessment, a more complete physical examination (conducted by a study clinician 
licensed to make medical diagnoses and listed as an investigator on the Form FDA 1572) may 
occur. An initial assessment of clinical response will be obtained to include maximum 
temperature in the past 24 hours and an assessment of improved activity and appetite since 
initiating antibiotic therapy. 
An assessment of clinical response will occur at each follow-up visit. The assessment will 
include parental documentation of maximum temperature in the preceding 24 hours; 
normalization of respiratory rate; presence and extent of cough; occurrence of medically 
attended visits including visits to the ED, primary care physician, and urgent care; 
hospitalizations; use of non-study systemic antibiotics (parenteral or oral); and occurrence of 
surgical procedures. Vital signs (temperature, pulse and respiratory rates) will be collected at 
the enrollment visit and at each follow-up visit.   
Solicited event assessments will include an assessment of solicited events occurring from the 
time of enrollment through the last visit, Visit 3. All subjects will complete a subject memory aid 
from the time of enrollment through Visit 3. Subject memory aids will be reviewed with the 
subject’s parents for any discrepancies or missing data and will be returned to the subject’s 
parent(s). 


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8.2 
Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations 
No clinical laboratory studies will be performed as part of this protocol.  
8.2.2 Special Assays or Procedures 
N/A 
8.2.3 Specimen Preparation, Handling, and Shipping 
N/A 
8.2.3.1 Instructions for Specimen Preparation, Handling, and Storage 
Specific instructions will be included in the Manual of Procedures (MOP) 
If the subject’s parent/legal guardian consents to future use, clinical site personnel will obtain 
throat swabs and arrange collection of stool samples. Routine throat swabs will be obtained by 
site personnel at the time of enrollment, Outcome Assessment Visit #1, and Outcome 
Assessment Visit #2. Please refer to the MOP for specific details regarding type of swab. At 
enrollment, parents will be provided with a stool collection kit and instructions for sample 
collection. Parents will collect a stool sample within 2 days after the enrollment visit and within 2 
days prior to or 2 days after Outcome Assessment Visits #1 and #2. Parents will be instructed to 
immediately store the stool sample in their home freezer. Parents will be instructed to bring the 
stool samples to the clinical site or sites will arrange pickup (e.g., courier services) at the 
subject’s home. Samples will be transported to the laboratory in a freezer pack; once at the 
laboratory, samples will be stored at approximately -20°C, with temporary excursions up to -5˚C 
allowable. The microbial community composition has been shown to remain consistent in fecal 
samples stored at room temperature for up to 24 hours and for up to 14 days at 4°C or -20°C.9,10 
Moreover, samples are stable for up to 6 months at -80°C.9,10   
Throat Swabs  
Samples will be stored locally in an approximately 4˚C refrigerator, with temporary excursions 
up to 8˚C allowable, for up to 48 hours after collection.  Samples will then be held in a -20˚C 
freezer (with temporary excursions to -5˚C allowable) until they are batch shipped to the DMID 
Clinical Materials Services (CMS). 
 
Stool Samples 
Stool specimens will be obtained at Visits 1, 2, and 3. Specimens will be collected by retention of 
a fecal containing diaper or by collection of stool into a sterile cup that will be provided to the 
subject’s parent/legal guardian. Samples can be collected within 2 days of the study visit and 
maintained in a freezer in the subject’s home until sent by courier or collected by study staff and 
transported to the study site. A minimum of approximately 2 teaspoons of stool will be collected. 
Samples will be stored locally and shipped according to Section 8.2.3.2. 
 
 


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8.2.3.2 Specimen Shipment 
Specific instructions will be included in the Manual of Procedures (MOP) 
All specimens will be transported or shipped via courier under controlled conditions to the site (if 
collected at a home visit or affiliated clinic) and stored according to the MOP in order to maintain 
appropriate storage temperatures.  When requested, samples will be batch-shipped to the DMID 
CMSper instructions in the MOP. 


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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Amoxicillin, amoxicillin-clavulanate, cefdinir are approved drugs with established and well-
described safety profile. The most prevalent of the drug side effects include:  
Amoxicillin: Common side effects include rash, diarrhea, nausea, vomiting, and 
mucocutaneous candidiasis. Rare side effects include: 
• 
Cardiovascular: hypersensitivity angiitis 
• 
Central nervous system: agitation, anxiety, behavioral changes, confusion, dizziness, 
headache, hyperactivity (reversible), insomnia, seizure  
• 
Dermatologic: acute generalized exanthematous pustulosis, erythema multiforme, 
exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria  
• 
Gastrointestinal: dental discoloration (brown, yellow, or gray; rare), hemorrhagic colitis, 
melanoglossia, pseudomembranous colitis 
• 
Genitourinary: crystalluria 
• 
Hematologic & oncologic: agranulocytosis, anemia, eosinophilia, hemolytic anemia, 
leukopenia, thrombocytopenia, thrombocytopenic purpura  
• 
Hepatic: cholestatic hepatitis, cholestatic jaundice, hepatitis (acute cytolytic), increased 
hepative enzymes 
• 
Hypersensitivity: anaphylaxis 
• 
Immunologic: serum sickness-like reaction 
Amoxicillin-clavulanate (in addition to side effects listed for amoxicillin above): Common 
side effects include diaper rash, abdominal discomfort, and loose stools. Other reported side 
effects include: 
• 
Dermatologic: diaper rash, urticaria  
• 
Gastrointestinal: abdominal distress, diarrhea, loose stools, nausea, vomiting  
• 
Genitourinary: vaginitis 
• 
Infection: candidiasis, vaginal mycosis 
• 
Rare but important or life-threatening: cholestatic jaundice, headache, hepatotoxicity 
(idiosyncratic), increased liver enzymes, increased serum alkaline phosphatase, 
prolonged prothrombin time, thrombocythemia, vasculitis (hypersensitivity) 
Cefdinir: Common side effects include rash, abdominal pain, nausea, vomiting, diarrhea, 
headache, and mucocutaneous candidiasis.  Other side effects include: 
• 
Central nervous system: headache 
• 
Endocrine & metabolic: decreased serum bicarbonate, glycosuria, hyperglycemia, 
hyperphosphatemia, increased gamma-glutamyl transferase, increased lactate 
dehydrogenase 
• 
Genitourinary: Proteinuria, occult blood in urine, urine alkalinization 
• 
Hematologic: eosinophilia, lymphocytopenia, lymphocytosis, thrombocythemia, anemia 
• 
Hepatic: increased serum alkaline phosphatase, increased serum ALT 


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• 
Rare but important or life-threatening: anaphylaxis, anorexia, blood coagulation disorder, 
bloody diarrhea, cholestasis, conjunctivitis, erythema multiforme, erythema nodosum, 
fulminant hepatitis, hemolytic anemia, hepatitis (acute), interstitial pneumonitis 
(idiopathic), pseudomembranous colitis, renal failure (acute), and Stevens-Johnson 
syndrome 
As amoxicillin, amoxicillin-clavulanate, cefdinir are approved drugs with long prescribing history, 
NIAID does not expect that any new drug related safety signal will be detected in this trial. As 
such, the safety data collection will be targeted to only collect protocol defined SAEs and 
Suspected Unexpected Serious Adverse Reaction (SUSAR, See Section 9.2.2). 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1 Adverse Events 
Adverse Event (AE): International Conference on Harmonisation (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. FDA defines 
an AE as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product. 
As the safety profile of amoxicillin, amoxicillin-clavulanate, and cefdinir are well established, and 
this trial is not powered to detect new, unknown safety signals, there will be no unsolicited AE 
collection during this study and only protocol-defined SAE’s will be collected. 
Solicited adverse events that are common and known to occur following administration of the 
study product. Solicited adverse events will be recorded daily for the duration of the study (See 
Table 3) . In addition to the solicited adverse events specified in Table 3, the presence and 
severity of cough (Table 2) will be recorded daily for the duration of the study to allow for 
assessment of the resolution of pneumonia symptoms.  
9.2.2 Serious Adverse Events 
Serious Adverse Event (SAE): 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 event1,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
                                               
 
1 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 subject 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. 


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• 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions,  
• 
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 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. 
 
Protocol defined SAEs: For this protocol, only the following SAEs will be collected, regardless 
of the relationship to study drug.  
• 
Death that is not the result of trauma or accident 
• 
Anaphylaxis 
• 
Laryngospasm or bronchospasm within 1 day after initiation of the study treatment 
• 
Stevens-Johnson syndrome  
• 
Severe erythema multiforme 
• 
Toxic epidermal necrolysis 
SAEs must be graded for severity and assessed for relationship to study product (see 
definitions below).   
Severity of Event:  SAEs will be assessed by a licensed study physician listed on the Form 
FDA 1572 as the site principal investigator or appropriate sub-investigator using a protocol-
defined grading system.  For events not included in the protocol-defined grading system, the 
following guidelines will be used to quantify severity: 
• 
Mild (Grade 1):  Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• 
Moderate (Grade 2):  Events result in a low level of inconvenience or concern with 
therapeutic measures.  Moderate events may cause some interference with functioning 
and daily activities. 
• 
Severe (Grade 3):  Events interrupt the subject’s usual daily activities and may require 
systemic drug therapy or other treatment.  Severe events are usually incapacitating. 
Relationship to Study Product:  The study physician’s assessment of an SAE's relationship to 
study product is part of the documentation process, but it is not a factor in determining what is or 
is not reported in this study.  If there is any doubt as to whether a clinical observation is an SAE, 
the event should be reported.  The relationship to study product must be assessed for SAEs 
using the terms: related or not related. In a clinical trial, the study product must always be 
suspect. To help assess, the following guidelines are 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. 


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• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.3 Procedures to be Followed in the Event of Abnormal Clinical Findings 
 
Subjects will be evaluated for the adequacy of clinical response and for the occurrence of 
solicited events at the outcome assessment visits.  If a serious adverse event is suspected, or if 
clinical response is inadequate, subjects will be referred immediately to their primary provider or 
local ED/urgent care.  
9.3 
Reporting Procedures 
9.3.1 Serious Adverse Events 
All SAEs will be: 
• 
Assessed for severity and causal relationship by a physician listed on the Form FDA 1572 
as the principal investigator (PI) or sub-investigator. 
• 
Recorded on the appropriate SAE report form. 
• 
Followed through resolution by a study physician. 
• 
Reviewed by the safety monitor, the DSMB (periodic review unless associated), DMID 
Medical Monitor, and the local IRB. 
Death, life-threatening events, hospitalization or prolongation of existing hospitalization, and 
other important medical events are part of the efficacy endpoints of this trial and will not be 
reported or collected as SAEs, unless meeting the SAE reporting criteria included in Section 
9.2.2. 
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: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
In addition to the SAE form, selected SAE data fields must also be entered into the Emmes 
AdvantageEDC web-based data entry system. Refer to the Manual of Procedures for details 
regarding this procedure. Timelines for submission of an SAE form are as follows:  
• 
All non-accidental deaths and life-threatening events, regardless of relationship, will be 
recorded on the SAE form and sent by fax within 24 hours of site awareness of the death 
or event.  
• 
All other SAEs, regardless of relationship, will be reported via fax by the site within 24 
hours of becoming aware of the event.  


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Other supporting documentation of the event may be requested by the pharmacovigilance 
contractor and should be provided as soon as possible. 
 
All SAEs will be followed until satisfactory resolution or until the PI or sub-investigator deems 
the event to be chronic or the subject to be stable.  
9.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site principal investigator or appropriate sub-investigator, DMID, 
the Investigational New Drug (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 site principal investigators (i.e., all 
principal investigators to whom the sponsor is providing drug under its IND(s) or under any 
principal investigator’s IND(s)) 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 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. 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
Study related solicited events will be followed until the final study visit.  
9.5 
Halting Rules 
9.5.1 Study Halting Rules 
Subject safety data will be reviewed on an ongoing basis. If any of the following events occur 
while a subject is on study, then enrollment will be stopped and data will be reviewed. A 
decision to proceed or to terminate the trial will be made in consultation with the DSMB, 
NIH/NIAID/DMID, and the clinical investigators.  
 
Further study enrollment will be halted for DSMB review/recommendation if any of the following 
are reported: 
• 
Hospitalization of 2 subjects (or >2% if more than 100 subjects enrolled) that requires 
intensive care or leads to death due to persistent/worsening pneumonia 


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• 
More than five subjects (>5% if more than 100 subjects enrolled) experience 
persistent/worsening pneumonia within 3 days of initiation of study treatment 
o Persistent/worsening pneumonia is a clinical diagnosis, accompanied by the 
following clinical characteristics: 
 
administration of non-study directed systemic antibiotic therapy, 
hospitalization, or surgical intervention (e.g., placement of a chest tube) 
for persistent/worsening pneumonia 
• 
More than 2 subjects (>2% if more than 100 subjects enrolled) experience an SAE of 
laryngospasm, bronchospasm, or anaphylaxis within 1 day after initiation of study 
treatment that is suspected to be related to study product. 
• 
More than 2 subjects (>2% if more than 100 subjects enrolled) experience death (that is 
not the result of trauma or accident) within 3 days of initiation of study treatment and is 
suspected to be related to study product. 
9.5.2 Individual Halting Rules (Termination of Study Product Administration) 
 
Study product administration may be discontinued if any of the following criteria are met: 
• 
Any clinical adverse event (AE), intercurrent illness, or other medical condition occurs 
that, in the opinion of the investigator, continued receipt of study product would not be in 
the best interest of the subject; 
• 
New onset of illness or condition that meets exclusion criteria 
• 
Inadequate clinical response that requires off-study antimicrobial therapy.  
o Subjects who require off-study antimicrobial therapy will be defined as having an 
inadequate clinical response.  
Subjects may stop study drug treatment at any time of their own volition or at the advice of their 
treating provider or the study investigators.  Subjects who stop study product for any reason will 
be regarded as having withdrawn from treatment but not as having withdrawn from the study 
(i.e, subjects will be asked to continue to participate in follow-up visits). All subjects with an 
inadequate clinical response will be referred to a non-study healthcare provider for evaluation 
and possible treatment outside of the clinical study.  
 
At the time of withdrawal, subjects will undergo an early termination visit if they are not willing to 
participate in the remaining follow-up visits 
9.6 
Safety Oversight 
9.6.1 Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID. The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial 
or other conflict of interest related to the study. The DSMB will consist of members with 
appropriate expertise to contribute to the interpretation of the data from this trial. 
The DSMB will review study progress and participant, clinical and safety data at the following 
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• 
Annually at the completion of each respiratory disease season;  
• 
Final review meeting, approximately 6-8 months after clinical database lock to review the 
cumulative unblinded safety and efficacy data for this trial.  The data will be provided in a 
standard summary format; 
• 
Ad hoc when a halting rule is met, for immediate concerns regarding observations during 
the study, or as needed. 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. Procedures for DSMB reviews/meetings will be defined in the 
charter. The DSMB will review applicable data to include, but not limited to, study progress and 
participant, clinical, and safety data that may include enrollment and demographic information, 
medical history, concomitant medications, physical assessments, dosing, solicited events, and 
SAEs. Additional data may be requested by the DSMB, and interim statistical reports may be 
generated as deemed necessary and appropriate by DMID. The DSMB may receive data in 
aggregate and presented by group. The DSMB will meet and review this data at scheduled time 
points or ad hoc as needed during the study as defined in the DSMB charter. As an outcome of 
each review/meeting, the DSMB will make a recommendation as to the advisability of 
proceeding with study product administration, and to continue, modify, or terminate the study. 
DMID, the PI, or the DSMB chair may convene the DSMB on an ad hoc basis according to 
protocol criteria or if there are immediate concerns regarding observations during the course of 
the study. The DMID Medical Monitor is empowered to stop enrollment and study treatment if 
the halting criteria is met or in case of any safety concern. The DMID Medical Monitor will be 
responsible for reviewing SAEs in real time. The DSMB will review SAEs on a regular basis and 
ad hoc during the study. 


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10 
CLINICAL MONITORING 
10.1 
Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subject protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that the study is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures.  DMID, the sponsoring agency, or its designee will conduct site-
monitoring visits as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID in a separate monitoring plan 
and may be made more frequently as directed by DMID.  Monitoring visits will include, but are 
not limited to, review of regulatory files, accountability records, eCRFs, informed consent forms, 
medical and laboratory reports, and protocol and GCP compliance.  Site monitors will have 
access to the study site, study personnel, and all study documentation according to the DMID-
approved site monitoring plan.  Study monitors will meet with site principal investigators to 
discuss any issues noted  
 
In this protocol, a ‘specific site’ is defined as one in which resources for the study (e.g., study 
staff, storage facilities, drug storage, or study records) are housed.  Monitoring visits will focus 
on these specific sites to ensure compliance with DMID and ICH/GCP policies, procedures, and 
guidelines. In addition, a significant number of visits will occur in non-site locations, such as 
community clinics or home visits. These ‘generic’ sites will not be considered part of the site 
monitoring plan. 
 


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11 
STATISTICAL CONSIDERATIONS 
This is a randomized double-blinded placebo-controlled trial comparing a strategy of short course 
(5-days) vs. standard course (10-days) oral beta-lactam antibiotic therapy with respect to 
desirability of outcome in children with CAP.  
The trial is designed using Response Adjusted for Days of Antibiotic Risk (RADAR).11 RADAR 
utilizes a superiority trial design under the conceptual framework, evaluating whether a strategy 
of short course antibiotic therapy is better than the standard course strategy when considering 
the totality of all of the important outcomes (adequacy of the clinical response, adverse events, 
and the duration of antibiotic use).  
All trial participants are assigned a desirability of outcome ranking (DOOR), constructed as 
follows:  
I. 
Each subject is evaluated according to the ordinal clinical response (Refer to Section 
3.2.1) 
II. 
DOOR is assigned according to two rules: 
(i) When comparing two subjects with different ordinal clinical responses, the subject 
with a better ordinal clinical response receives a higher rank. 
(ii) When comparing two subjects with the same ordinal clinical response, the subject 
with fewer days of antibiotic use receives a higher rank. Days of antibiotic use are 
defined as the number of days for which the subject is reported to have taken at 
least one dose of non-placebo study product or a non-study product systemic 
antibiotic. 
During analyses, the distributions of DOORs are compared between short-course and standard-
course strategies. The sum of the probability that a randomly selected participant from the short 
course strategy will have a better DOOR than a randomly selected participant from the standard 
course strategy plus one-half the probability that the DOORs are equal is estimated using a 
confidence interval.  
The primary outcome measure is the DOOR at Outcome Assessment Visit #1 (defined above). 
DOOR at Outcome Assessment Visit #1 is computed using data from Day 1 to Day 5. 
Secondary outcome measures include: 
1. DOOR at Outcome Assessment Visit #2. 
2. Resolution of symptoms (a component of DOOR) at each outcome assessment visit, 
defined as the absence of fever, tachypnea, or cough of grade 2 or higher. 
3. Adequate clinical response rates (a component of DOOR) at each outcome assessment 
visit, defined as the absence of a medically attended visit to an ED or outpatient clinic or 
hospitalization for persistent or worsening pneumonia that occurs after randomization and 
receipt of at least one dose of study drug. 
4. Frequency of solicited events at each outcome assessment visit, as listed in Table 3.  


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5. Medically attended visits to ED or clinic; hospitalizations; surgical procedures; and receipt 
of non-study systemic antibiotics for persistent or worsening pneumonia (as defined 
above) at each outcome assessment visit 
i. 
Individual event types (e.g., medical visits, hospitalizations, surgical procedures, 
and receipt of non-study systemic antibiotics) will be compared between treatment 
groups. 
6. Medically attended visits to ED or clinic; hospitalizations; surgical procedures; and receipt 
of non-study systemic antibiotics for all causes at each outcome assessment visit  
i. 
Individual event types (e.g., medical visits, hospitalizations surgical procedures, and 
receipt of non-study systemic antibiotic) will be compared between treatment 
groups. 
Exploratory outcome measures include: 
1. DOOR at Outcome Assessment Visits #1 and #2, when increasing the threshold in 
assigning different ranks due to differing numbers of days of antibiotic use from a one 
day difference to a two, three, four, or five day difference.  
11.1 
Study Hypothesis 
• 
Null: the sum of the probability that a subject assigned to the 5-day arm will have 
a higher DOOR than if assigned to the 10-day arm plus one-half the probability of 
equal DOORs is 50% (i.e., no difference in DOOR).  
11.2 
Sample Size Considerations 
The primary study sample size is based on a superiority test of the null hypothesis in 11.1, 
under an assumed alternative hypothesis that the sum of the probability that a subject assigned 
to the 5-day arm will have a higher DOOR than if assigned to the 10-day arm plus one-half the 
probability of equal DOORs is 60% (p=60%).  
A sample size of 360 (180 per arm) provides 90% power using a 2-sided alpha=0.05 with a 
Wilcoxon Mann-Whitney U test. If p=65% or 70%, then a total sample size of 160 (80 per arm) 
or 90 (45 per arm), respectively, would be required.  The sample size is inflated by ~10% based 
on an estimate from a similar study, in order to account for loss to follow-up resulting in a total 
sample size of 400 (200/arm).  
11.3 
Planned Interim Analyses  
11.3.1 Safety Review  
A Data Safety Monitoring Board (DSMB) appointed by NIAID will monitor this protocol.  Interim 
safety review may include enrollment and demographic information, medical history, concomitant 
medications, physical assessments, dosing, and protocol specific SAEs and SUSAR. Additional 
data may be requested by the DSMB, and interim statistical reports may be generated as deemed 
necessary and appropriate by DMID. The DSMB may receive data in aggregate and presented 
by treatment group. The DSMB will meet and review this data at scheduled time points or ad hoc 
as needed during the study as defined in the DSMB charter. As an outcome of each 


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review/meeting, the DSMB will make a recommendation as to the advisability of proceeding with 
the study or to modify or terminate the study.  
Additionally, the study will be monitored to determine if any of the halting rules described in 
Section 9.5 are met. 
11.3.1 Interim Analysis of Efficacy, Futility, and Safety 
One interim analysis, described below, will be performed and reported to the DSMB after at least 
30% of the targeted subjects have completed the study.  The interim analysis will inform DSMB 
decisions regarding stopping early for efficacy, futility, or safety. 
For the interim analysis, a snapshot of the study database will be unblinded and used to 
conduct  analyses as follows.  An ITT analysis including all enrolled subjects in the snapshot of 
the study database will be performed, testing the null hypothesis provided in Section 11.1 using 
the methods described in Section 11.4.1, with the modification that the Haybittle-Peto boundary 
(p<0.001) will be used when concluding statistical significance.  The study may be stopped early 
for efficacy only if statistical significance is detected in that test.  In the event of statistical 
significance, sensitivity analyses using complete case and according-to-protocol cohorts (CC-V1 
and ATP-V1, as described below) as well as worst case analyses will be included in the DSMB 
report to further guide decisions for stopping for efficacy.   
A 95% confidence interval for the probability that a randomly selected subject will have a better 
DOOR if assigned to the 5-day strategy (vs. the standard strategy) will be estimated but not 
used to inform DSMB decisions about stopping early for efficacy. Predicted interval plots 
(PIPS)12,13 will be constructed to provide the DSMB with a prediction of the trial results were the 
trial to continue as planned under varying assumptions regarding future data (e.g., current trend 
continues, null hypothesis is true, alternative hypothesis is true). 
The DSMB will also be provided with the following: 
1. For subjects that have completed Outcome Assessment Visit #1 and have received at least 
one dose of study product, a between arm difference in the overall outcome (DOOR) via a 
cumulative difference plot with respective confidence bands for Outcome Assessment Visit 
#1 
2. For subjects that have completed Outcome Assessment Visit #1 and have received at least 
one dose of study product, a forest plot of 95% confidence intervals for the risk difference of 
adequate clinical response as well as the following interventions for persistent or worsening 
pneumonia: (1) ED/clinic visits, (2) hospitalizations, (3) surgical procedures, and (4) non-
study systemic antibiotics at Outcome Assessment Visit #1.  
3. For subjects that have completed Outcome Assessment Visit #1 and have received at least 
one dose of study product, a forest plot of 95% confidence intervals for the risk difference of 
lack of resolution of symptoms as well as the following: (1) Oral, rectal, axillary or tympanic 
temperature ≥38.3˚C (100.9˚F), confirmed by repeat measurement after at least 15 minutes, 
in the 24 hours preceding Outcome Assessment Visit #1, unless attributed to a new process 
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breaths/minute for children <24 months of age and >40 breaths/minute for children 24-71 
months of age) at Outcome Assessment Visit #1, and (3) Presence of cough Grade 2 or 3 at 
Outcome Assessment Visit #1. 
4. For subjects that have completed Outcome Assessment Visit #1 and have received at least 
one dose of study product, a forest plot of 95% confidence intervals for the risk difference of 
each solicited event and with the risk difference of any solicited event, for each severity 
threshold (mild or greater, moderate or greater, or severe) for Outcome Assessment Visit 
#1. 
11.4 
Final Analysis Plan 
The primary analysis of the primary endpoint will be performed according to an intention-to-treat 
(ITT) approach and include all randomized subjects.  As (secondary) sensitivity analyses of the 
primary endpoint, complete case analyses using the CC-V1 / ATP-V1 cohorts (defined below) 
and a worst case analysis using the ITT cohort of the primary endpoint will be performed. 
Additional analyses may be performed and are described in detail in the Statistical Analysis 
Plan. 
Intention-to-Treat Cohort: All randomized participants, analyzed as randomized.  Subjects that 
have not received at least one dose of study product will have adequate clinical response and 
its sub-components treated as missing. 
Complete Case Cohorts (CC): Subjects in a CC analysis are analyzed as randomized, but 
excluded from analysis if missing data prevents assigning an unambiguous value to the DOOR 
endpoint or if the subject has not received at least one dose of study product.  The CC-V1 
cohort will consist of all subjects with sufficient data to define unambiguously the Visit #1 
DOOR.  The CC-V2 cohort will consist of all subjects with sufficient data to define 
unambiguously the Visit #2 DOOR.   
According-to-Protocol Cohorts (ATP): Subjects in an ATP analysis require at least one dose of 
study product each day from Day 1 to Day 5 and furthermore subjects will excluded from 
analysis if missing data prevents assigning an unambiguous value to the DOOR endpoint  The 
ATP-V1 cohort will restrict subjects to those with sufficient data to define unambiguously the 
Visit #1 DOOR.  The ATP-V2 cohort will restrict subjects to those with sufficient data to define 
unambiguously the Visit #2 DOOR.   
Details of what constitutes sufficient data to assign an unambiguous value to DOOR will be 
specified in the statistical analysis plan. 
11.4.1 Primary Analysis 
For the primary analyses, the DOORs will be compared between the 5- and 10-day arms. The 
sum of the probability that a randomly selected subject will have a better DOOR if assigned to 
the 5-day arm for Outcome Assessment Visit #1 plus one-half the probability of equal DOORs 
for Outcome Assessment Visit #1 will be estimated. The null hypothesis to be tested is that the 
probability is equal to 0.50 (lack of superiority of short-course therapy).  The primary analysis 
will be carried out using the ITT cohort, with missing DOOR values (treated as continuous) 


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imputed using multiple imputation, utilizing linear regression models corresponding to relevant 
observed data (baseline covariates and observed DOOR components from an early termination 
visit, if available). The Mann-Whitney U statistic will be combined across the datasets to give the 
test statistic and Rubin’s Rules used to define distribution of the test statistic under the  null 
hypothesis.  The test of the null hypothesis will be two-sided with a Type I error of 0.05.  A point 
estimate of the estimand will be computed by dividing combined test statistic by the number of 
pairwise comparisons and a confidence interval of the estimand will be computed by inverting 
the described test of the null hypothesis. 
Note: Subjects will be asked to confirm fever with repeat testing after approximately 15 minutes; 
for analysis purposes, subjects lacking a repeat measurement will be considered as having 
developed fever.  
11.4.2 Secondary Analyses 
All secondary and exploratory analyses will use a Type I error rate of 0.05 and will not correct 
for multiple comparisons.  All tests will be two-sided. 
Secondary analyses will include: 
• 
Analysis of DOOR at Outcome Assessment Visit #2, performed as ITT in an analogous 
manner to the primary analysis. 
• 
Sensitivity Analyses for the DOOR at Outcome Assessment Visits #1 and #2 ITT 
analyses.  (1) CC analyses.  (2) ATP analyses.  (3) Worst case analyses: all imputations 
of missing data will be the worst case (result in the lowest possible DOOR given 
available information) for subjects in the 5-day arm and best case for subjects in the 10-
day arm.  Sensitivity analyses will test the null hypothesis using the Mann-Whitney U 
Test, estimate using U divided by the number of pairwise comparisons, and will compute 
confidence intervals by (1) inverting the Mann-Whitney U Test and (2) using a non-
parametric bootstrap. 
• 
Separately for Outcome Assessment Visit #1 and #2, using CC cohorts, a forest plot of 
95% confidence intervals for the risk difference of each solicited event and the risk 
difference of any solicited, for each severity threshold (mild or greater, moderate or 
greater, or severe).  Tests for differences in proportions between treatment arms will be 
given by Fisher’s exact tests. 
• 
Separately for Outcome Assessment Visit #1 and #2, using CC cohorts, a forest plot of 
95% confidence intervals for the risk difference of lack of resolution of symptoms as well 
as the following: (1) Oral, rectal, axillary or tympanic temperature ≥38.3˚C (100.9˚F), 
confirmed by repeat measurement after at least 15 minutes, in the 24 hours preceding 
the Outcome Assessment Visit, unless attributed to a new process that is unrelated to 
the prior diagnosis of pneumonia; (2) Elevated respiratory rate (RR >50 breaths/minute 
for children <24 months of age and >40 breaths/minute for children 24-71 months of 
age) at the time of the Outcome Assessment Visit; and (3) Presence of cough Grade 2 
or 3 at the Outcome Assessment Visit.  Tests for differences in proportions between 
treatment arms will be given by Fisher’s exact tests. 


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• 
Separately for Outcome Assessment Visit #1 and #2, using CC cohorts, a forest plot of 
95% confidence intervals for the risk difference of adequate clinical response as well as 
the following interventions for persistent or worsening pneumonia: (1) ED/clinic visits, (2) 
hospitalizations, (3) surgical procedures, and (4) non-study systemic antibiotics.  Tests 
for differences in proportions between treatment arms will be given by Fisher’s exact 
tests. 
• 
Separately for Outcome Assessment Visit #1 and #2, using CC cohorts, a forest plot of 
95% confidence intervals for the risk difference of adequate clinical response as well as 
the following interventions for all causes: (1) ED/clinic visits, (2) hospitalizations, (3) 
surgical procedures, and (4) non-study systemic antibiotics.  Tests for differences in 
proportions between treatment arms will be given by Fisher’s exact tests. 
• 
Analysis of the ordinal clinical response at Outcome Assessment Visits #1 and #2.  The 
ITT analysis will treat the ordinal clinical response as Normal distributed and use multiple 
imputation to compute confidence intervals for the mean ordinal clinical response by 
treatment assignment and to test whether the mean ordinal clinical response varies by 
treatment assignment.  CC, ATP, and worst case analyses of the ordinal clinical 
response will be performed; separately for Outcome Assessment Visit #1 and #2, a 
cumulative difference plot with respective 95% confidence bands for the ordinal clinical 
response (and an associated result from a Mantel-Hantzel chi-square test on the ordinal 
clinical response) will be computed. Non-inferiority analyses of the ordinal clinical 
response at Outcome Assessment Visits #1 and #2 using the ITT cohort, to be specified 
in the statistical analysis plan, may be carried out. 
11.4.3 Exploratory Analyses 
Increased RADAR thresholds sensitivity analysis.  In the primary RADAR/DOOR analysis, if two 
subjects from separate treatment arms have an equal ordinal clinical response but a difference 
in the duration of antibiotic use of at least 𝑘𝑘= 1  day, RADAR assigns a more favorable 
response to the subject with fewer days of antibiotic use.  For a sensitivity analysis, the effect of 
increasing the minimum difference in the duration of antibiotic use (𝑘𝑘= 2,3,4, or 5) before a 
favorable response is given to the subject with shorter duration of antibiotic use will be explored.  
For each value of 𝑘𝑘, bootstrapped confidence intervals of the probability of more favorable 
DOOR due to assignment to the 5-day antibiotic course will be computed and plotted versus 𝑘𝑘.  
Analysis will be performed separately for DOOR at Outcome Assessment Visit #1 and DOOR at 
Outcome Assessment Visit #2.  Analyses will be performed using CC-V1/CC-V2 cohorts. 
Other exploratory analyses, if required, to be specified in the statistical analysis plan. 
 
 


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of subjects.  Each site will permit authorized representatives of the 
DMID, its designees, and appropriate regulatory agencies to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, 
and evaluation of the study safety and progress.  These representatives will be permitted 
access to all source data, which include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.  Data collection forms will be derived from the eCRFs and be provided by the Statistical 
and Data Coordinating Center (SDCC). 
 


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the participating VTEU sites 
and its subcontractors are responsible for conducting routine quality assurance (QA) and quality 
control (QC) activities to internally monitor study progress and protocol compliance.  The site 
principal investigator will provide direct access to all trial-related sites, source data/data 
collection forms, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities.  The site principal investigator will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site. 
The SDCC 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. 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 
Ethical Standard 
The site principal investigator will ensure that this trial 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 site principal 
investigator’s Institution will hold a current Federal Wide Assurance (FWA) issued by the Office 
of Human Research Protection (OHRP) for federally funded research. 
14.2 
Institutional Review Board 
Prior to enrollment of subjects into this trial, the approved protocol and informed consent form 
will be reviewed and approved by the appropriate IRB listed on its FWA. 
The responsible official for the IRB will sign the IRB letter of approval of the protocol prior to the 
start of this trial and a copy will be provided to DMID.  The IRB Federal Wide Assurance number 
will be provided to DMID. 
Should amendments to the protocol be required, the amendments will be written by the sponsor 
and provided to the site principal investigator for submission to the IRB. 
14.3 
Informed Consent Process 
14.3.1 Informed Consent 
The site principal investigator will choose subjects in accordance with the eligibility criteria 
detailed in Section 5.  Before any study procedures are performed, subjects must sign an 
informed consent form that complies with the requirements of 21 CFR Part 50 and 45 CFR 46 
and the local IRB. 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation.  Before any study procedures 
are performed, subjects will receive a comprehensive explanation of the proposed study 
procedures and study interventions/products, including the nature and risks of the trial, alternate 
therapies, any known AEs, the investigational status of the components, and the other elements 
that are part of obtaining proper informed consent.  Subjects will also receive a detailed 
explanation of the proposed use and disclosure of their protected health information.  Subjects 
will be allowed sufficient time to consider participation in the trial, after having the nature and 
risks of the trial explained to them, and have the opportunity to discuss the trial with their family, 
friends or legally authorized representative or think about it prior to agreeing to participate. 
Informed consent forms describing in detail the study interventions/products, study procedures, 
risks and possible benefits are given to subjects.  The informed consent form must not include 
any exculpatory statements.  Informed consent forms will be IRB-approved and subjects will be 


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asked to read and review the appropriate document.  Upon reviewing the appropriate document, 
the site principal investigator (or designee) will explain the research study to subjects and 
answer any questions that may arise.  Subjects must sign the informed consent form, and 
written documentation of the informed consent process is required prior to starting any study 
procedures/interventions being done specifically for the trial, including administering study 
product. 
DMID will provide the site principal investigator, in writing, any new information that significantly 
impacts the subjects' risk of receiving the investigational product.  This new information will be 
communicated by the site principal investigator to subjects who consent to participate in the trial 
in accordance with IRB requirements.  The informed consent document will be updated and 
subjects will be re-consented per IRB requirements, if necessary. 
Local IRB requirements will govern subject recruitment efforts and pre-enrollment activities. 
Subjects will be given a copy of all informed consent forms that they sign. By signing the 
informed consent form, subjects agree to complete all evaluations required by the trial, unless 
the subject withdraws voluntarily, or is withdrawn or terminated from the trial for any reason. 
The rights and welfare of subjects will be protected by emphasizing to subjects that the quality 
of their medical care will not be adversely affected if they decline to participate in or withdraw 
from this trial. 
14.3.2 Informed Consent/Assent Process (in Case of a Minor) 
Parents or legal guardians will be asked to provide consent for the participation of their children 
as outlined in Section 14.3.1. Since all eligible children in this study are <7 years of age, formal 
written assent will not be obtained; nevertheless, study personnel will explain the study to the 
child in age appropriate terms and will ensure that the well being of participating children is 
protected.  
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
This study is focused on children age 6-71 months of age and will include all racial, ethnic , and 
gender/sex categories. 
14.5 
Subject Confidentiality 
Subjects will have code numbers and will not be identified by name. Subject confidentiality is 
strictly held in trust by the participating investigators, their staff, and the sponsor(s) and their 
agents.  
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence.  No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All information provided by the Sponsor and all data and information generated by the 
participating site as part of the trial (other than a subject’s medical records) will be kept 


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confidential by the site principal investigator and other study personnel to the extent permitted 
by law. This information and data will not be used by the site principal investigator or other study 
personnel for any purpose other than conducting the trial. These restrictions do not apply to: (1) 
information which becomes publicly available through no fault of the site principal investigator or 
other study personnel; (2) information which is necessary to disclose in confidence to an IRB 
solely for the evaluation of the trial (3) information which is necessary to disclose in order to 
provide appropriate medical care to a study subject; or (4) study results which may be published 
as described in Section 16. If a written contract for the conduct of the trial which includes 
confidentiality provisions inconsistent with this statement is executed, that contract’s 
confidentiality provisions shall apply rather than this statement. 
The study monitor, applicable regulatory authorities, such as the FDA, or other authorized 
representatives of the sponsor may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this study.  The clinical study site will permit 
access to such records. 
14.6 
Future Use of Stored Specimens 
Subjects will be asked for permission to keep any samples for use in future research studies, 
such as analyzing the impact of antibiotic usage of the microbiome. Some samples may be 
stored at the local site and some at a central clinical storage facility. Samples may be shared 
with other investigators at other institutions, provided that appropriate human subject protection 
plans are in place. The samples will not be sold or used directly for production of any 
commercial product. No human genetic tests will be performed on samples. Each sample will be 
encoded (labeled) only with a barcode and a unique tracking number to protect subject’s 
confidentiality.  
There are no benefits to subjects in the collection, storage and subsequent research use of 
specimens. Reports about future research done with subject’s samples will not be kept in their 
health records.  
Subjects may be given the option to decide if they want their samples to be used for future 
research or have their samples destroyed at the end of the trial. The subject’s decision can be 
changed at any time prior to the end of the trial by notifying the study doctors or nurses in 
writing. However, if the subject originally consents to future use and subsequently changes 
his/her decision, any data from a previously collected sample may still be used for this research. 


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15 
DATA HANDLING AND RECORD KEEPING 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness 
of the data reported.   
Data collection forms will be derived from the eCRFs and provided by the SDCC to the sites to 
record and maintain data for each subject enrolled in the study.  All source documents should 
be completed in a neat, legible manner to ensure accurate interpretation of data.  Permanent ink 
is required to ensure clarity of reproduced copies.  When making a change or correction, the 
original entry should be crossed out with a single line, and the change should be initialed and 
dated.  Do not erase, overwrite, or use correction fluid or tape on the original.  
Data reported in the eCRF should be consistent with the data collection form/source documents 
or the discrepancies should be documented.   
The sponsor and/or its designee will provide guidance to investigators on making corrections to 
the data collection forms and eCRFs.   
15.1 
Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete.  Adverse events must be 
graded, assessed for severity and causality, and reviewed by the site PI or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI.  During the study, the investigator must maintain complete and accurate 
documentation for the study. 
Emmes will serve as the Statistical and Data Coordinating Center for this study and will be 
responsible for data management, quality review, analysis, and reporting of the study data. 
15.2 
Data Capture Methods 
Clinical data (including solicited events and concomitant medications) and clinical laboratory 
data will be entered into a 21 CFR Part 11-compliant Internet Data Entry System (IDES) 
provided by Emmes.  The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate.  Clinical data will be entered directly from the source documents.  
15.3 
Types of Data 
Data for this study will include clinical, safety, and outcome measures. 
 


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15.4 
Timing/Reports 
A final report will be prepared following the availability of all the safety and efficacy data. Interim 
statistical reports may be generated as deemed necessary and appropriate by DMID. Safety 
and efficacy summary reports may be generated for the DSMB. 
After full analysis and final reporting is complete, and upon request and DMID approval, the 
SDCC will provide the participating sites with a summary of results by treatment group and/or 
subject treatment assignments. In this regard, the participating sites requesting such information 
to share with study subjects must do so in compliance with their respective IRB guidelines. 
15.5 
Study Records Retention 
Records and documents pertaining to the conduct of this study, including data collection forms, 
source documents, consent forms, laboratory test results, and medication inventory records 
shall be retained for 2 years after a marketing application is approved for the drug; or, if an 
application is not approved for the drug, until 2 years after shipment and delivery of the drug for 
investigational use is discontinued and FDA has been so notified. The site must contact DMID 
for authorization prior to the destruction of any study records. Informed consent forms for future 
use will be maintained as long as the sample exists. 
15.6 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements.  The noncompliance may be either on the part of 
the subject, the investigator, or the study site staff.  As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, section 5.1.1 
5.20 
Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity.  All deviations must be promptly reported to DMID, via the 
Emmes IDES  
All deviations from the protocol must be addressed in study subject source documents.  A 
completed copy of the DMID Protocol Deviation Form (IDES form) must be maintained in the 
regulatory file, as well as in the subject’s source document.  Protocol deviations must be sent to 
the local IRB/IEC per their guidelines.  The site PI/study staff is responsible for knowing and 
adhering to their IRB/IEC requirements. 


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16 
PUBLICATION POLICY 
Following completion of the study, the investigator is expected to publish the results of this 
research in 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 
policy requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov*, which is sponsored by the National Library of Medicine.  Other biomedical 
journals are considering adopting similar policies.  It is the responsibility of DMID to register this 
trial in an acceptable registry.  Any clinical trial starting enrollment after 01 July 2005 must be 
registered on or before subject enrollment.  For trials that began enrollment prior to this date, 
the ICMJE member journals will require registration by 13 September 2005, before considering 
the results of the trial for publication. 
 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome.  Studies designed for other purposes, 
such as to study pharmacokinetics or major toxicity (e.g., Phase I trials), would be exempt from 
this policy. 
 


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17 
LITERATURE REFERENCES 
 
1 
Rudan, I., Bosch-Pinto, C. & Biloglav, Z. Epidemiology and etiology of childhood pneumonia. Bull 
World Health Organ 86, 408 (2008). 
2 
Kronman, M., Hersh, A. & Feng, R. Ambulatory visit rates and antibiotic prescribing for children 
with pneumonia. Pediatrics 127, 411-418 (2011). 
3 
CDC. Pneumonia hospitalizations among young children before and after introduction of 
pneumococcal conjugate vaccine - United States, 1997-2006. Morbidity and Mortality Weekly 
Report, 3 (2009). 
4 
Jain, S. et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N 
Engl J Med 372, 835-845 (2015). 
5 
Bradley, J., Byington, C. & Shah, S. The management of community-acquired pneumonia in 
infants and children over 3 months of age: clinical practice guidelines by the Pediatric Infectous 
Diseases Society and the Infectious Diseases Society of America. Clinical Infectious Diseases 
53, e25-e76 (2011). 
6 
Haider, B. A., Saeed, M. A. & Bhutta, Z. A. Short-course versus long-course antibiotic therapy for 
non-severe community-acquired pneumonia in children aged 2 months to 59 months. Cochrane 
Database of Systematic Reviews, CD005976 (2008). 
7 
Hazir, T., BNisar, Y. & Abbasi, S. Comparison of oral amoxicillin with placebo for the treatment of 
World Health Organization-defined nonsevere pneumonia in children 2-59 months: a multi-center, 
double-blind, randomized, placebo-controlled trial in Pakistan. Clinical Infectious Diseases 53, 
293 (2011). 
8 
Seppala, H. et al. The Effect of changes in the consumption of macrolide antibiotics on 
erythromycin resistance in group A streptococci in Finland. . New England Journal of Medicine 
337, 441-446 (1997). 
9 
Lauber, C., Zhou, N., Gordon, J., Knight, R. & Fierer, N. Effect of storage conditions on the 
assessment of bacterial community structure in soil and human-associated samples. FEMS 
Microbiology Letters 307, 80-86 (2010). 
10 
Carroll, I., Ringel-Kulka, T., Siddle, J., Lklaenhammer, T. & Y, R. Characterization of the fecal 
microbiota using high-throughput sequencing reveals a stable microbial community during 
storage. PLoS ONE 7, e46953 (2012). 
11 
Evans, S. R. et al. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration 
of Antibiotic Risk (RADAR). Clin Infect Dis 61, 800-806 (2015). 
12 
Evans, S., Li, L. & Wei, L. Data monitoring in clinical trials using prediction. Drug Inform Journal 
41, 73-742 (2007). 
13 
Li, L., Evans, S., Uno, H. & Wei, L. A graphical tool for data monitoring in clinical trials. Statistical 
Biopharmaceutical Research (2009). 
 


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APPENDIX A – SCHEDULE OF EVALUATIONS 
 
 
 
 
 
Initial treatment of 
CAP and 
Eligibility 
Screening1 
Enrollment 
Visit 
Receipt of 
Study Agent2 
Outcome 
Assessment 
Visit #1 
Outcome 
Assessment 
Visit #2 
Early 
Termination 
Visit (as 
applicable) 
Visit Number 
 
1 
 
2 
3 
 
Visit Day 
Days -5 to 1 
Day -3 to -1 
Days 1-5 
Day 6-10 
Day 19-25 
 
Screening and Enrollment 
 
 
 
 
 
 
Initially prescribed antibiotic therapy 
X 
 
 
 
 
 
Review of electronic medical records to assess eligibility3 
X 
 
 
 
 
 
Phone contact with parent/guardian to assess eligibility  
X 
 
 
 
 
 
Obtain Informed Consent  
 
X 
 
 
 
 
Review Eligibility Criteria 
 
X 
 
 
 
 
Medical History4 
 
X 
 
X 
X 
X 
Concomitant Medications 
 
X 
 
X 
X 
X 
Vital Signs (temperature, pulse, respiratory rate)  
 
X 
 
X 
X 
X 
Physical Assessment5 
 
X 
 
X 
X 
X 
Assess clinical response to initial antibiotic therapy 
 
X 
 
 
 
 
Enrollment and Randomization 
 
X 
 
 
 
 
Dispense study agent2 
 
X 
 
 
 
 
Distribute Memory Aid and Study-Related Materials 
 
X 
 
 
 
 
Follow-up 
 
 
 
 
 
 
Receipt of study agent 
 
 
X 
 
 
 
Collection of study product bottle 
 
 
 
X 
X7 
X7 
Review of electronic medical record to assess clinical 
response6 
 
 
 
X 
X 
X 
Review Memory Aid 
 
 
 
X 
X 
X 
Assess clinical response to therapy 
 
 
 
X 
X 
X 
Assess solicited events 
 
 
 
X 
X 
X 
Collection of Future Use Samples (if consented) 
 
 
 
 
 
 
Throat Swab 
 
X 
 
X 
X 
 
Collection of stool  
 
X 
 
X 
X 
 


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Footnotes: 
1. 
Day -5 is defined as the date on which the diagnosis of CAP is made and treatment with oral beta-lactam therapy is initiated.   
2. 
Study drug will be either a continued course of the oral antibiotic therapy that was initially prescribed (oral amoxicillin, amoxicillin-clavulanate, or cefdinir) or a 5 day course of 
matching placebo, which will begin on Day 1. 
3. 
Electronic medical records will be used to preliminarily assess eligibility, including:  age of the subject; diagnosis of CAP (a diagnosis of “pneumonia” is sufficient) without 
additional diagnoses of bronchiolitis or croup; initial antibiotic therapy for CAP with sufficient dose (i.e., prescription of amoxicillin or amoxicillin/clavulanate with an amoxicillin 
dose of 80-100 mg/kg/day or prescription of cefdinir of 12-16 mg/kg/day); absence prescription of any other antibiotic therapy ≤7 days before the diagnosis of CAP; absence of 
initial antibiotic therapy for CAP with combination therapy (i.e., amoxicillin, amoxicillin/clavulanate or cefdinir plus one or more additional antibiotics),; absence of a history of 
allergy to amoxicillin or oral cephalosporin antibiotics (except cefaclor); absence of radiographic findings of complicated pneumonia (pleural effusion, lung abscess, or 
pneumatocele) on the initial chest radiograph (if obtained) or any subsequent chest radiograph; absence of hospitalization for pneumonia during day 1-5 of antibiotic therapy for 
CAP; absence of blood or pleural fluid culture positive for S. aureus or group a streptococcus; absence of history of other conditions as described on the exclusion criteria; any 
other condition that in the judgment of the investigator precludes participation because it could affect the safety of the subject; current participation in any other clinical trial. 
4. 
Medical history will include acute or chronic medical disorders of the head, eyes, ears, nose, throat, mouth, cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, 
kidney, urologic system, nervous system, blood, lymph nodes, endocrine system, musculoskeletal system, skin, and genital/reproductive tract.  A history of any allergies, cancer, 
immunodeficiency and autoimmune disease will be solicited. The history will include capture of sociodemographic data. 
5. 
A physical assessment will be performed to determine general appearance and hydration status; vital signs, including temperature, pulse, and respiratory rate; an assessment of 
work of breathing, and presence of skin rash. This can be performed by a nurse, advanced practice nurse, physician assistant, pr physician. 
6. 
Study staff will make a preliminary EHR-based assessment of clinical response to determine whether any of the following events occurred after initiation of study drug:  a 
medically attended visit to an ED or outpatient clinic; receipt of non-study antibiotic [parenteral or oral]; treatment for a local pneumonia complication, including drainage of pleural 
fluid, placement of a chest tube, or video assisted thoracoscopic surgery. 
7. 
If not collected at previous visit. 

SAP_001.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 14-0079 
Study Title: 
A Phase IV Double-Blind, Placebo-Controlled, 
Randomized Trial to Evaluate 
Short Course vs. Standard Course Outpatient 
Therapy of Community Acquired Pneumonia in 
Children (SCOUT-CAP) 
 
NCT02891915 
 
Version 2.0 
 
DATE: 24FEB2020 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL 
 
 


Statistical Analysis Plan - DMID Protocol: 14-0079 
Version 2.0 
24FEB2020 
- ii - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 14-0079 
Development Phase: 
Phase IV 
Products: 
Amoxicillin, amoxicillin-clavulanate, cefdinir and matching 
placebos 
Form/Route: 
Oral suspensions 
Indication Studied: 
Community Acquired Pneumonia 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
04OCT2016 
Clinical Trial Completion Date: 
TBD 
Date of the Analysis Plan: 
24FEB2020 
Version Number: 
2.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is 
confidential. This information may not be disclosed to third parties without written authorization from Division of Microbiology 
and Infectious Diseases. This report may not be reproduced, stored in a retrieval system or transmitted in any form or by any 
means - electronic, mechanical, recording or otherwise - without the prior authorization from Division of Microbiology and 
Infectious Diseases. This document must be returned to Division of Microbiology and Infectious Diseases upon request. 
 


Statistical Analysis Plan - DMID Protocol: 14-0079 
Version 2.0 
24FEB2020 
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TABLE OF CONTENTS 
STUDY TITLE ............................................................................................................................... II 
TABLE OF CONTENTS ...............................................................................................................III 
LIST OF ABBREVIATIONS ...................................................................................................... VII 
1. 
PREFACE .....................................................................................................................1 
2. 
INTRODUCTION ........................................................................................................2 
2.1. 
Purpose of the Analyses ................................................................................................2 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................3 
3.1. 
Study Objectives ...........................................................................................................3 
3.1.1. 
Primary Objectives .......................................................................................................3 
3.1.2. 
Secondary Objectives ...................................................................................................3 
3.1.3. 
Exploratory Objectives .................................................................................................3 
3.2. 
Endpoints ......................................................................................................................3 
3.2.1. 
Primary Endpoints ........................................................................................................3 
3.2.2. 
Secondary Endpoints ....................................................................................................3 
3.2.3. 
Exploratory Endpoints ..................................................................................................4 
3.3. 
Study Definitions and Derived Variables .....................................................................4 
4. 
INVESTIGATIONAL PLAN .......................................................................................7 
4.1. 
Overall Study Design and Plan .....................................................................................7 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ........................8 
4.3. 
Selection of Study Population ......................................................................................9 
4.3.1. 
Inclusion Criteria ..........................................................................................................9 
4.3.2. 
Exclusion Criteria .........................................................................................................9 
4.3.3. 
Reasons for Withdrawal .............................................................................................10 
4.4. 
Treatments ..................................................................................................................10 
4.4.1. 
Treatments Administered ............................................................................................10 
4.4.2. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................10 
4.4.3. 
Blinding ......................................................................................................................11 
4.5. 
Study Variables ...........................................................................................................11 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................15 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................16 


Statistical Analysis Plan - DMID Protocol: 14-0079 
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TABLE OF CONTENTS (continued) 
- iv - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
6.1. 
General Principles .......................................................................................................16 
6.2. 
Timing of Analyses .....................................................................................................16 
6.3. 
Analysis Populations ..................................................................................................16 
6.3.1. 
Intention-to-Treat Analysis (ITT) Cohort ...................................................................17 
6.3.2. 
Complete Case (CC) Cohorts .....................................................................................18 
6.3.3. 
According-to-Protocol (ATP) Cohorts .......................................................................18 
6.3.4. 
Safety Analysis Population .........................................................................................18 
6.4. 
Covariates and Subgroups ..........................................................................................18 
6.5. 
Missing Data ...............................................................................................................18 
6.5.1. 
Adequate Clinical Response to OAV#1 or OAV#2 ...................................................19 
6.5.2. 
Fever at OAV#1 or OAV#2 ........................................................................................21 
6.5.3. 
Resolution of Symptoms at OAV#1 or OAV#2 .........................................................22 
6.5.4. 
Most Severe Solicited Event at OAV#1 and OAV#2 .................................................22 
6.5.5. 
Ordinal Clinical Response at OAV#1 or OAV#2 .......................................................23 
6.5.6. 
Number of Days of Antibiotic Use at OAV#1 or OAV#2 .........................................24 
6.5.7. 
Desirability of Outcome Ranking (DOOR) at OAV#1 or OAV#2 ............................25 
6.6. 
Interim Analyses and Data Monitoring ......................................................................26 
6.6.1. 
Predicted Interval Plots (PIPs) ....................................................................................27 
6.7. 
Multicenter Studies .....................................................................................................28 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................29 
7. 
STUDY SUBJECTS ...................................................................................................30 
7.1. 
Disposition of Subjects ...............................................................................................30 
7.2. 
Protocol Deviations ....................................................................................................30 
8. 
EFFICACY EVALUATION ......................................................................................31 
8.1. 
Primary Efficacy Analysis ..........................................................................................31 
8.1.1. 
Primary Analysis of DOOR at Outcome Assessment Visit #1...................................31 
8.2. 
Secondary Efficacy Analyses .....................................................................................32 
8.2.1. 
Analysis of DOOR at Outcome Assessment Visit #2, Performed as ITT in an 
Analogous Manner to the Primary Analysis ...............................................................32 
8.2.2. 
Sensitivity Analyses for the DOOR at Outcome Assessment Visits #1 and #2 
ITT analyses. ...............................................................................................................34 
8.2.2.1. 
Complete Case Analysis of the DOOR at Outcome Assessment Visit #1 .................34 


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8.2.2.2. 
Complete Case Analysis of the DOOR at Outcome Assessment Visit #2 .................35 
8.2.2.3. 
According-to-Protocol Analysis of the DOOR at Outcome Assessment Visit 
#1 ................................................................................................................................35 
8.2.2.4. 
According-to-Protocol Analysis of the DOOR at Outcome Assessment Visit 
#2 ................................................................................................................................35 
8.2.2.5. 
Worst Case Analysis of the DOOR at Outcome Assessment Visit #1 .......................35 
8.2.2.6. 
Worst Case Analysis of the DOOR at Outcome Assessment Visit #2 .......................35 
8.2.3. 
Solicited Events at Outcomes Assessment Visits #1 and #2 ......................................35 
8.2.4. 
Resolution of Symptoms at Outcomes Assessment Visits #1 and #2 ........................36 
8.2.5. 
Adequate Clinical Response at Outcomes Assessment Visits #1 and #2 ...................36 
8.2.6. 
Ordinal Clinical Response at Outcomes Assessment Visits #1 and #2 ......................36 
8.2.6.1. 
ITT Analyses of OCR at Outcomes Assessment Visit #1 ..........................................37 
8.2.6.2. 
ITT Analyses of OCR at Outcomes Assessment Visit #2 ..........................................37 
8.2.6.3. 
Complete Case Analysis of the OCR at Outcome Assessment Visit #1 ....................38 
8.2.6.4. 
Complete Case Analysis of the OCR at Outcome Assessment Visit #2 ....................38 
8.2.6.5. 
According-to-Protocol Analysis of the OCR at Outcome Assessment Visit 
#1 ................................................................................................................................38 
8.2.6.6. 
According-to-Protocol Analysis of the OCR at Outcome Assessment Visit 
#2 ................................................................................................................................38 
8.2.6.7. 
Worst Case Analysis of the OCR at Outcome Assessment Visit #1 ..........................38 
8.2.6.8. 
Worst Case Analysis of the OCR at Outcome Assessment Visit #2 ..........................38 
8.2.7. 
Additional Analysis of Cough ....................................................................................38 
8.3. 
Exploratory Efficacy Analyses ...................................................................................39 
8.3.1. 
Complete Case Evaluation of DOOR at Outcome Assessment Visit #1, 
Minimum Required Difference in Days for Antibiotic Use “Tie-breaking” 
Varies k=1,2,3,4,5, or infinity.....................................................................................39 
8.3.2. 
Stratified (ITT) Analyses of DOOR at Outcome Assessment Visit #1 ......................39 
8.3.3. 
As Treated Analysis of Effect of Number of Days of Antibiotic Use on OCR 
at Outcome Assessment Visit #1 and Outcome Assessment Visit #2 ........................39 
8.4. 
Imputation of Missing Data ........................................................................................40 
8.4.1. 
Multiple Imputation of Missing Ordinal Clinical Response and DOOR at 
Outcome Assessment Visit #1 and Outcome Assessment Visit #2 ............................40 
9. 
SAFETY EVALUATION ..........................................................................................44 
9.1. 
Demographic and Other Baseline Characteristics ......................................................44 


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9.1.1. 
Concurrent Illnesses and Medical Conditions ............................................................44 
9.1.2. 
Prior and Concurrent Medications ..............................................................................44 
9.2. 
Measurements of Treatment Compliance ...................................................................44 
9.3. 
Adverse Events ...........................................................................................................44 
9.3.1. 
Solicited Events ..........................................................................................................45 
9.3.2. 
Unsolicited Adverse Events ........................................................................................45 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................45 
9.5. 
Vital Signs and Physical Evaluations .........................................................................45 
9.6. 
Concomitant Medications ...........................................................................................45 
9.7. 
Other Safety Measures ................................................................................................46 
10. 
OTHER ANALYSES .................................................................................................47 
11. 
REPORTING CONVENTIONS ................................................................................48 
12. 
TECHNICAL DETAILS ............................................................................................49 
13. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................50 
14. 
REFERENCES ...........................................................................................................51 
15. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................52 
APPENDICES ...............................................................................................................................53 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................54 
APPENDIX 2. FIGURE MOCK-UPS ......................................................................................118 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................136 
APPENDIX 4. NCA TEMPLATE ............................................................................................157 
 


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LIST OF ABBREVIATIONS 
ACR 
Adequate Clinical Response 
AE 
Adverse Event/Adverse Experience 
ATC 
Anatomical Therapeutic Classification 
ATP 
According-to-Protocol 
CAP 
Community Acquired Pneumonia 
C 
Celsius 
CAR 
Clinical Agents Repository 
CC 
Complete Case 
CC-V1 
Complete Case at Outcome Assessment Visit #1 Analysis Population 
CC-V1 
Complete Case at Outcome Assessment Visit #2 Analysis Population 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, DHHS 
DOOR 
Desirability of Outcome Ranking 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
EHR 
Electronic Health Record 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
h 
Hours 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDES 
Internet Data Entry System 


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LIST OF ABBREVIATIONS (continued) 
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IDSA 
Infectious Diseases Society of America 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-to-Treat 
kg 
Kilogram 
L 
Liter 
MAR 
Missing at Random 
MAV 
Medically Attended Visit 
MCAR 
Missing Completely at Random 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
MOP 
Manual of Procedures 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
N 
Number (typically refers to subjects) 
NIH 
National Institutes of Health, DHHS 
OAV 
Outcome Assessment Visit 
OCR 
Ordinal Clinical Response 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PT 
Preferred Term 
QA 
Quality Assurance 
QC 
Quality Control 
RADAR 
Response Adjusted for Days of Antibiotic Risk 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SCOUT 
Short Course Therapy for Urinary Tract Infections in Children 


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SDCC 
Statistical and Data Coordinating Center 
SOC  
System Organ Class 
Std 
Standard Deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
US 
United States 
USP 
United States Pharmacopeia 
 


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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “A Phase IV Double-Blind, Placebo-Controlled, 
Randomized Trial to Evaluate Short Course vs. Standard Course Outpatient Therapy of 
Community Acquired Pneumonia in Children (SCOUT-CAP)” (DMID protocol 14-0079) 
describes and expands upon the statistical information presented in the protocol. 
This document describes all planned analyses and provides reasons and justifications for these 
analyses. It also includes sample tables, figures, and listings planned for the final analyses. 
Regarding the final analyses and Clinical Study Report (CSR), this SAP follows the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH) Guidelines, as indicated in Topic E3 (Structure and Content of Clinical Study 
Reports), and more generally is consistent with Topic E8 (General Considerations for Clinical 
Trials) and Topic E9 (Statistical Principles for Clinical Trials). The structure and content of the 
SAP provides sufficient detail to meet the requirements identified by the FDA and ICH, while all 
work planned and reported for this SAP will follow internationally accepted guidelines published 
by the American Statistical Association and the Royal Statistical Society for statistical practice. 
This document contains four sections: (1) a review of the study design, (2) general statistical 
considerations, (3) comprehensive statistical analysis methods for efficacy and safety outcomes, 
and (4) a list of proposed tables and figures. Any deviation from this SAP will be described and 
justified in protocol amendments and/or in the CSR, as appropriate. The reader of this SAP is 
encouraged to also review the study protocol for details on conduct of the study and the 
operational aspects of clinical assessments. 


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2. 
INTRODUCTION 
This is a Phase IV, blinded, placebo-controlled, multi-center, randomized trial with a primary 
objective to compare the composite overall outcome (Desirability of Outcome Ranking, DOOR) 
among children 6-71 months of age with community acquired pneumonia (CAP) assigned to a 
strategy of short course (5 days) vs standard course (10 days) outpatient beta-lactam therapy. 
Subjects are randomized 1:1 to either an additional 5 day course of their initially prescribed 
antibiotic (10 days total antibiotic therapy), or 5 days of a matching placebo (5 days total 
antibiotic therapy). Randomization is stratified by 1) age group (<24 months vs. 24-71 months), 
2) initially prescribed antibiotic (amoxicillin vs. amoxicillin-clavulanate vs. cefdinir), and 3) 
treatment site (emergency department vs. outpatient clinic/urgent care facility). Randomization is 
not stratified by clinical site. 
The study follows a variety of clinical outcomes including 1) persistence of fever, tachypnea, or 
cough; 2) medically attended visits for persistent or worsening pneumonia; and 3) solicited 
events. 
2.1. 
Purpose of the Analyses 
A composite of the clinical outcomes and number of days of antibiotic use is used to define the 
DOOR and assess the overall superiority of short course treatment. Superiority of DOOR using 
clinical outcomes from the first 5 study days and at Outcome Assessment Visit #1 will be the 
primary analysis. Superiority of DOOR using clinical outcomes from the first 18 days and at 
Outcome Assessment Visit #2 will be a secondary analysis. For both analyses, all components of 
the DOOR will also be analyzed individually. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objectives 
1. To compare the composite overall outcome (Desirability of Outcome Ranking, DOOR) 
among children 6-71 months of age with CAP assigned to a strategy of short course (5 
days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome 
Assessment Visit #1 (Study Day 8 +/- 2 days). 
3.1.2. 
Secondary Objectives 
1. To compare the composite overall outcome (DOOR) among children 6-71 months of age 
with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) 
outpatient beta-lactam therapy at Outcome Assessment Visit #2 (Study Day 22 +/- 3 
days). 
2. To compare the resolution of symptoms (a component of DOOR) among children 6-71 
months of age with CAP assigned to a strategy of short course (5 days) vs standard 
course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2. 
3. To compare the clinical response (a component of DOOR) among children 6-71 months 
of age with CAP assigned to a strategy of short course (5 days) vs standard course (10 
days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2. 
4. To compare solicited events (a component of DOOR) among children 6-71 months of age 
with CAP assigned to a strategy of short course (5 days) vs standard course (10 days) 
outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2. 
5. To compare medically attended visits to Emergency Departments (ED) or outpatient 
clinics, hospitalizations, surgical procedures, and receipt of non-study systemic 
antibiotics (components of the clinical response) among children 6-71 months of age with 
CAP assigned to a strategy of short course (5 days) vs standard course (10 days) 
outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2. 
3.1.3. 
Exploratory Objectives 
1. To examine the robustness of results of DOOR comparisons when increasing the 
threshold in assigning different ranks due to differing numbers of days of antibiotic use 
from a 1 day difference to a 2, 3, 4, or 5 day difference. 
3.2. 
Endpoints 
3.2.1. 
Primary Endpoints 
The primary endpoint/outcome measure is the DOOR at Outcome Assessment Visit #1. 
3.2.2. 
Secondary Endpoints 
Secondary outcome measures include: 


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1. DOOR at Outcome Assessment Visit #2 
2. Resolution of symptoms (a component of DOOR) at each outcome assessment visit, 
defined as the absence of fever, tachypnea, or cough of grade 2 or higher. 
3. Adequate clinical response rates (a component of DOOR) at each outcome assessment 
visit, defined as the absence of a medically attended visit to an ED or outpatient clinic or 
hospitalization for persistent or worsening pneumonia that occurs after randomization and 
receipt of at least one dose of study drug. 
4. Frequency of solicited events at each outcome assessment visit, as listed in Table 3. 
5. Medically attended visits to ED or clinic; hospitalizations; surgical procedures; and 
receipt of non-study systemic antibiotics for persistent or worsening pneumonia (as 
defined below) at each outcome assessment visit 
i. 
Individual event types (e.g., medical visits, hospitalizations, surgical procedures, 
and receipt of non-study systemic antibiotics) will be compared between treatment 
groups. 
6. Medically attended visits to ED or clinic; hospitalizations; surgical procedures; and 
receipt of non-study systemic antibiotics for all causes at each outcome assessment visit 
i. 
Individual event types (e.g., medical visits, hospitalizations surgical procedures, and 
receipt of non-study systemic antibiotic) will be compared between treatment 
groups. 
3.2.3. 
Exploratory Endpoints 
1. DOOR at Outcome Assessment Visits #1 and #2, when increasing the threshold in 
assigning different ranks due to differing numbers of days of antibiotic use from a 1 day 
difference to a 2, 3, 4, or 5 day difference. 
3.3. 
Study Definitions and Derived Variables 
DOOR is defined as follows: 
1. Each subject is evaluated according to the ordinal composite outcome (See Table 1) and 
assigned an outcome rank ranging from 1-8. The ordinal outcome is referred to elsewhere 
in the SAP as the ordinal clinical response (OCR). 
2. Desirability of Outcome Ranking (DOOR) is then assigned according to two rules: 
i. 
When comparing two subjects with different ordinal responses, the subject with a 
better ordinal response receives a higher rank. 
ii. 
When comparing two subjects with identical ordinal responses, the subject with 
fewer days of antibiotic use receives a higher rank. 
The ordinal composite outcome involves an assessment of whether the subject has an adequate 
clinical response and whether they have experienced any solicited events as defined in Table 1. 


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Table 1: 
Ordinal Outcome 
 
Adequate clinical response1 
(Assessed at Outcome Assessment 
Visits #1 and #2) 
Solicited events3 
(Assessed at Outcome Assessment 
Visits #1 and #2) 
1 
Yes, with resolution of symptoms2 
None 
2 
Yes, with resolution of symptoms2 
Mild (Grade 1) 
3 
Yes, with resolution of symptoms2 
Moderate (Grade 2) 
4 
Yes, with resolution of symptoms2 
Severe (Grade 3) 
5 
Yes, with persistent symptoms of fever, tachypnea, or cough 
None or any grade 
6 
No, with ED/clinic visit but no hospitalization 
None or any grade 
7 
No, with hospitalization 
None or any grade 
8 
Death from any cause 
1 Adequate clinical response is defined as the absence of a medically attended visit to an ED or outpatient clinic or 
hospitalization for persistent or worsening pneumonia that occurs after randomization and receipt of at least one 
dose of study drug. 
• Persistent or worsening pneumonia is defined as receipt of a non-study systemic antibiotic for pneumonia or 
treatment for a complication of pneumonia, including drainage of pleural fluid, placement of a chest tube, video 
assisted thoracoscopic surgery, or thoracotomy procedures. 
• Note: Receipt of a non-study antibiotic will not be regarded as satisfying this definition if it is related to a new 
diagnosis that is unrelated to the prior diagnosis of pneumonia. 
2 Resolution of symptoms is defined as the absence of all of the following: 
• Oral, rectal, axillary, or tympanic temperature ≥38.3˚C (100.9˚F), confirmed by repeat measurement after at least 
15 minutes, in the 24 hours preceding the Outcome Assessment Visit, unless attributed to a new process that is 
unrelated to the prior diagnosis of pneumonia; 
• Elevated respiratory rate (RR >50 breaths/minute for children <24 months of age and >40 breaths/minute for 
children 24-71 months of age) at the time of the Outcome Assessment Visit; 
• Presence of cough grade 2 or 3 at the Outcome Assessment Visit, defined as Grade 0 (no cough), Grade 1 
(Occasional coughing [less than 4 times hourly]), Grade 2 (frequent coughing [4 or more times an hour], interferes 
with sleep), Grade 3 (almost constant coughing (never free of cough), makes sleep nearly impossible);  
3 Solicited events will be captured daily until Outcome Assessment Visit #2; thereafter, parents/legal guardians will 
report symptoms based on memory aid and medical interview by study staff. For those with multiple solicited 
events, the ordinal response table will be based upon the most severe solicited event. 
Day 1: Day 1 begins at the time the first dose of study product is administered and ends at 11:59 
PM of that same day.  If a subject has no recorded receipt of study product at the time of the 
analysis, then Day 1 will be defined as the date 5 days after the date of initiation of the initial 
antibiotic. 
DOOR at Outcome Assessment Visit #1: Defined as above, using DOOR components from the 
following Study Days. 
Adequate Clinical Response: Day 1 – Day 5 
Resolution of Symptoms: 
o Fever as measured in the 24 hours prior to Outcome Assessment Visit #1. If a subject 
has a fever according to a single measurement, but no repeat measurement after at 
least 15 minutes has been performed, the subject will be analyzed as having a fever. If 
a subject has a fever according to the measurement taken as a part of vital signs 


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during Outcome Assessment Visit #1, the subject will be analyzed as having a fever 
at Outcome Assessment Visit #1.  If the vital signs measurement shows no fever, and 
the parental assessment of fever during the previous 24 hours is missing, then fever 
will be treated as missing. 
o Respiratory Rate and Cough: determined at Outcome Assessment Visit #1 
Solicited Events: Day 1 – Day 5 
Number of Days of Antibiotic Use: Day 1 – Day 5 
DOOR at Outcome Assessment Visit #2: Defined as above, using DOOR components from the 
following Study Days. 
Adequate Clinical Response: Day 1 – Day 18 
Resolution of Symptoms: 
o Fever as measured in the 24 hours prior to Outcome Assessment Visit #2. If a subject 
has a fever according to a single measurement, but no repeat measurement after at 
least 15 minutes has been performed, the subject will be analyzed as having a fever. If 
a subject has a fever according to the measurement taken as a part of vital signs 
during Outcome Assessment Visit #2, the subject will be analyzed as having a fever 
at Outcome Assessment Visit #2.  If the vital signs measurement shows no fever, and 
the parental assessment of fever during the previous 24 hours is missing, then fever 
will be treated as missing. 
o Respiratory Rate and Cough: determined at Outcome Assessment Visit #2 
Solicited Events: Day 1 – Day 18 
Number of Days of Antibiotic Use: Day 1 – Day 18 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a multi-center, randomized, double-blind, placebo-controlled, superiority clinical trial 
evaluating short course (5 day) vs. standard course (10 day) of oral beta-lactam antibiotic therapy 
(amoxicillin, amoxicillin-clavulanate, cefdinir) for treatment of CAP in children 6-71 months of 
age who have clinically improved prior to enrollment. The study will randomize approximately 
400 enrolled subjects to one of the two study arms (approximately 200 children in each arm) in 
order to reach 360 evaluable subjects. Subjects will be randomized (1:1) to receive either a 
standard course of the initially prescribed antibiotic (10 days) or a short course of the initially 
prescribed antibiotic (5 days) plus 5 days of matching placebo. 
The study will recruit potential subjects from children who are diagnosed with CAP and who are 
initiated on oral beta-lactam therapy (amoxicillin, amoxicillin-clavulanate, cefdinir) by 
healthcare providers in EDs, outpatient clinics, and urgent care centers at the study sites. Day -5 
is defined as the date on which oral beta-lactam therapy is initiated for a diagnosis of CAP. 
Potential subjects will be identified at any time following clinical diagnosis of pneumonia. These 
subjects will be assessed for eligibility and enrolled on Day -3 to -1 of their initially prescribed 
oral beta-lactam therapy. Subjects may also be enrolled on Day 1 (the first day of receipt of study 
agent) provided they have not yet received any doses of the healthcare provider-prescribed 
antibiotic therapy for that day. 
Visit 1: Enrollment Visit. Subjects who meet the eligibility criteria, and whose parent/guardian 
consents for participation in the study, will complete an Enrollment Visit on Day -3 to -1. 
Subjects satisfying the inclusion criteria with no exclusion criteria will be enrolled and 
randomized. Enrolled subjects will continue to receive the initially prescribed antibiotic through 
Day -1. The subjects’ parents/guardians will be instructed to contact study personnel if their 
child develops fever or worsening respiratory symptoms (worsening cough, increased work of 
breathing, any other concerning symptoms in the parents’ estimation) following enrollment. 
Randomization: Enrolled subjects will be randomized to short vs. standard course therapy at a 
1:1 ratio, with stratification by 1) age group (<24 months vs. 24-71 months), 2) initially 
prescribed antibiotic (amoxicillin vs. amoxicillin-clavulanate vs. cefdinir), and 3) treatment site 
(emergency department vs. outpatient clinic/urgent care facility). 
Intervention: Subjects will continue on the initially prescribed antibiotic through Day -1, until 
they have completed 5 days (i.e., 5 scheduled doses of once daily medication, 10 scheduled 
doses of twice daily medication) of antibiotic therapy [e.g., if a subject takes the first dose of 
antibiotic in the afternoon of Day -5, the first dose of study agent would occur on the afternoon 
of Day 1, providing 10 total scheduled doses of a twice daily prescribed antimicrobial]. The first 
day of receipt of study agent will be Day 1. Subjects assigned to standard course therapy will 
receive 5 additional days (10 doses) of the same initially prescribed antibiotic, with standardized 
twice-daily dosing. Subjects assigned to short course therapy will receive 5 more days (10 doses) 
of a matching placebo. Both the study agent and placebo may appear different than the 
commercial formulation the child originally received. The placebo will appear indistinguishable 
in color, taste, thickness, and consistency from the active antibiotic the child would otherwise 


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receive in the study. The study product will be labeled with a numerical code that masks site 
investigators, site staff, parent(s)/guardian(s) and children to the formulation. 
Follow-up and Assessment of Endpoints: Subjects will be scheduled for the following 
assessment visits: 
Visit 2: Outcome Assessment Visit #1, Day 6 to 10 (1-5 days after completing the study agent). 
Subjects will be evaluated for the components of the composite overall outcome, which include 
the adequacy of the subject’s clinical response; persistence of symptoms of fever, tachypnea, or 
cough; the occurrence of any solicited events; and the duration of antibiotic therapy (both study 
product/placebo and any additional oral or parenteral antibiotic therapy prescribed by study or 
non-study providers). 
Visit 3: Outcome Assessment Visit #2, Day 19 to 25 (14-20 days after completing the study 
agent). Subjects will be evaluated for the components of the composite overall outcome, which 
include the adequacy of the subject’s clinical response; persistence of symptoms of fever, 
tachypnea, or cough; the occurrence of any solicited events; and the duration of antibiotic 
therapy (both study product/placebo and any additional oral or parenteral antibiotic therapy 
prescribed by study or non-study providers). 
Subjects who are identified as having an inadequate clinical response prior to Outcome 
Assessment Visit #1 will be asked to complete Outcome Assessment Visits #1 and #2, in order to 
evaluate the occurrence of any solicited events and the duration of antibiotic therapy (both study 
product/placebo and any additional oral or parenteral antibiotic therapy prescribed by study or 
non-study providers). 
Subjects will be invited to contribute oropharyngeal and stool specimens at specified times 
throughout the study for future use. Additional informed consent will be obtained for future use 
sample collection. 
Figure 1: Schematic of the Study Design 
 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
In 2014, a randomized trial of short vs. standard course therapy in young children in Israel with 
CAP suspected to be of bacterial origin found a higher rate of treatment failure (40%) in subjects 
treated for only 3 days vs. subjects treated for 5 or 10 days (Greenberg 2014). The study was 
underpowered to detect a difference in treatment failure between subjects treated for 5 vs. 10 
days, but treatment failure did not occur in either group. 
The proposed study will test the effectiveness of short (5-day) vs. standard (10-day) course 
therapy in children who are diagnosed with CAP and initially treated in outpatient clinics, urgent 


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care facilities, and emergency departments. The study will specifically address whether short 
course therapy is superior to standard therapy among children that have clinically improved since 
diagnosis. If superior to standard course therapy, short course therapy could reduce antibiotic 
exposure among young children. We will use a study methodology similar to the SCOUT Study 
(“Short Course Therapy for Urinary Tract Infections in Children”)—a randomized, double-blind, 
placebo-controlled non-inferiority trial of short course antimicrobial therapy for urinary tract 
infection in children sponsored by NIAID through the “Targeted Clinical Trials to Reduce the 
Risk of Antimicrobial Resistance” initiative. However, the SCOUT-CAP trial will use a 
superiority study design using an ordinal composite overall outcome (Desirability of Outcome 
Ranking, DOOR, see Protocol Section 3.2.1 Primary Outcome Measures)—to test the hypothesis 
that short course (5 day) therapy is superior to standard course (10-day) beta-lactam therapy in 
children who have experienced early clinical improvement of pneumonia. 
The potential risk of short course therapy is that clinical outcomes may not be equivalent to 
standard course therapy. Specifically, the percent of children with adequate clinical response (or 
in this case, no relapse of illness) may be lower in children receiving short course therapy. 
Adequate clinical response can be defined as resolution or substantial improvement in clinical 
signs and symptoms (e.g., fever, cough, respiratory rate, work of breathing) and the lack of need 
for additional antibiotic therapy, additional contacts with the health care system, or surgical 
procedures for worsening pneumonia. The magnitude of this risk is not well established, 
although a study from Israel suggests it is small (Greenberg 2014); nevertheless, this degree of 
risk will be evaluated during this trial. 
4.3. 
Selection of Study Population 
Subjects who are diagnosed with CAP in emergency departments (EDs), urgent care facilities, 
and clinics will be screened for eligibility. Screening will continue until 400 subjects are enrolled 
cumulatively across all the study sites. The study will recruit potential subjects from children 
who are diagnosed with CAP and who are initiated on antibiotic therapy using oral beta-lactam 
therapy (amoxicillin, amoxicillin-clavulanate, cefdinir) by healthcare providers in EDs, 
outpatient clinics, and urgent care centers at the study sites. Potential subjects will be identified 
at any time following clinical diagnosis of pneumonia. Other forms and/or mechanisms of 
recruitment may also be used. The local IRB will approve recruitment materials prior to use. 
Subject Inclusion and Exclusion Criteria must be confirmed by a study clinician licensed to make 
medical diagnoses. 
No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Questions about eligibility will be directed toward the DMID Medical Officer. 
4.3.1. 
Inclusion Criteria 
For a list of inclusion criteria, see the most recent version of the Protocol. 
4.3.2. 
Exclusion Criteria 
For a list of exclusion criteria, see the most recent version of the Protocol. 


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4.3.3. 
Reasons for Withdrawal 
Subject Withdrawal 
Subjects’ parents/guardians may voluntarily withdraw their consent for study participation at any 
time and for any reason, without penalty. 
A subject may withdraw or be withdrawn from the study for any of the following reasons: 
• 
Withdrawal of consent 
• 
Subject lost to follow-up 
• 
Termination of the study 
• 
Any new information becomes available that makes further participation unsafe. 
Subjects who wish to withdraw from further study participation will be asked to continue to 
participate in follow-up visits. At the time of withdrawal, subjects will undergo an early 
termination visit, if they are not willing to participate in the remaining follow-up visits. 
Discontinuation of Treatment 
A subject may be discontinued from treatment and continue to be followed if any of individual 
halting rules (see Protocol) are met. 
4.4. 
Treatments 
4.4.1. 
Treatments Administered 
All active and placebo study products will be orally administered via oral dosing syringe or 
dosing cup. For older children in whom a dosing cup is preferred, parents will be instructed to 
measure the drug in the oral dosing syringe prior to transferring to the dosing cup. 
4.4.2. 
Method of Assigning Subjects to Treatment Groups (Randomization) 
Per International Conference on Harmonisation (ICH) guideline E6: Good Clinical Practice 
(GCP), screening records will be kept at each participating site to document the reason why an 
individual was screened, but failed trial entry criteria. The reasons why individuals failed 
screening will be recorded on screening logs maintained by each site. 
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled. Subjects will be assigned to either placebo or active study drug (the 
same antibiotic that they were prescribed for the first 5 days of treatment). After a subject is 
enrolled, they will be given a random treatment assignment of study product to either short 
course or standard course therapy. Randomization to short vs. standard course therapy will be at 
a 1:1 ratio (approximately 200 subjects per treatment group). Subjects will be stratified by age 
group <24 months vs. 24-71 months), type of initial antimicrobial therapy, and initial treatment 
in an ED or outpatient clinic/urgent care center. 
Enrollment of subjects will be performed online using the electronic data capture (EDC) system 
provided by the Statistical and Data Coordinating Center (SDCC). The list of randomized 
treatment assignments will be prepared by statisticians at the SDCC. The list will be used to 
assign each volunteer a treatment code after the necessary data have been entered into the EDC 


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system. A designated individual at each site will be provided with a treatment key, which links 
the treatment code to the actual treatment assignment, which will be kept in a secure place. 
Instructions for subject enrollment are included in the Manual of Procedures (MOP). Manual 
back-up randomization procedures are provided in the MOP for use in the event that the site 
temporarily loses access to the Internet or the online enrollment system is unavailable. 
4.4.3. 
Blinding 
This is a double-blind clinical trial. The study subjects and their parents/guardians, investigators, 
and study team staff will remain blinded to study treatment assignment throughout the study. The 
subjects and their families, investigators, and study team staff will not be blinded to which of the 
three antibiotics (amoxicillin, amoxicillin-clavulanate, cefdinir) the subject was initially 
prescribed. 
The study products and placebo will be prepared by the unblinded site Research Pharmacist. 
Only the pharmacy staff will be aware of the study product bottle assignments. For subjects 
randomized to standard course therapy, the pharmacy will provide the same medication 
prescribed initially. For subjects randomized to short course therapy, the pharmacy will provide a 
placebo that resembles the appearance (color and texture), flavor, and consistency of the active 
study product. All study products will be packaged with an identical appearance. Additional 
details regarding dispensing procedures will be included in the protocol-specific MOP. 
The study product will be labeled with a numerical code that masks site investigators, site staff, 
parent(s)/guardian(s) and children to the formulation. The unblinded site Research Pharmacist 
will be the only person to perform the unmasking if needed. Additional details regarding labeling 
procedures will be included in the protocol-specific MOP. 
During the consenting process it will be explained to the parents of any potential subjects that the 
study product (treatment or placebo) that will be provided for administration after Day 5, may or 
may not taste exactly the same as the originally prescribed medication, and that the look and 
smell may be slightly different because it might be supplied by a different manufacturer than that 
of the initially prescribed antibiotic. Parents will also be instructed that the amount or frequency 
of the prescribed study product has been made uniform across all study groups; therefore, the 
amount/frequency may be different than originally prescribed by their provider (e.g., receipt of 
once daily cefdinir is not excluded, but upon study entry, those subjects will receive either twice 
daily cefdinir or placebo). 
4.5. 
Study Variables 
The primary variables of interest in this study are the DOOR, ordinal clinical response, 
resolution of symptoms, adequate clinical response, and solicited events, as defined in 
Section 3.3. 
As the safety profile of amoxicillin, amoxicillin-clavulanate, and cefdinir are well established, 
and this trial is not powered to detect new, unknown safety signals, there will be no unsolicited 
event collection during this study and only protocol-defined SAEs and Suspected Unexpected 
Serious Adverse Reactions (SUSARs) will be collected. 


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For a complete list of SAEs that will be collected, regardless of the relationship to the study 
drug, see the Protocol. SAEs will be graded for severity and assessed for relationship to study 
product. 
See the Protocol for the schedule of events for this study. 


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Severity of Event: SAEs will be assessed by a licensed study physician listed on the Form FDA 
1572 as the site principal investigator or appropriate sub-investigator using a protocol-defined 
grading system. For events not included in the protocol-defined grading system, the following 
guidelines will be used to quantify severity: 
• 
Mild (Grade 1): Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• 
Moderate (Grade 2): Events result in a low level of inconvenience or concern with 
therapeutic measures. Moderate events may cause some interference with functioning and 
daily activities. 
• 
Severe (Grade 3): Events interrupt the subject’s usual daily activities and may require 
systemic drug therapy or other treatment. Severe events are usually incapacitating. 
Relationship to Study Product: The study physician’s assessment of an SAE's relationship to 
study product is part of the documentation process, but it is not a factor in determining what is or 
is not reported in this study. If there is any doubt as to whether a clinical observation is an SAE, 
the event should be reported. The relationship to study product must be assessed for SAEs using 
the terms: related or not related. In a clinical trial, the study product must always be suspect. To 
help assess, the following guidelines are 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. 
All SAEs will be: 
• 
Assessed for severity and causal relationship by a physician listed on the Form FDA 1572 
as the principal investigator (PI) or sub-investigator. 
• 
Recorded on the appropriate SAE report form. 
• 
Followed through resolution by a study physician. 
• 
Reviewed by the safety monitor, the DSMB (periodic review unless associated), DMID 
Medical Monitor, and the local IRB. 
Death, life-threatening events, hospitalization or prolongation of existing hospitalization, and 
other important medical events are part of the efficacy endpoints of this trial and will not be 
reported or collected as SAEs, unless meeting the SAE reporting criteria included in the 
Protocol. 
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. 
In addition to the SAE form, selected SAE data fields must also be entered into the EDC web-
based data entry system. Refer to the Manual of Procedures for details regarding this procedure. 
Timelines for submission of an SAE form are as follows: 


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• 
All non-accidental deaths and life-threatening events, regardless of relationship, will be 
recorded on the SAE form and sent by fax within 24 hours of site awareness of the death 
or event. 
• 
All other SAEs, regardless of relationship, will be reported via fax by the site within 24 
hours of becoming aware of the event.  
Other supporting documentation of the event may be requested by the pharmacovigilance 
contractor and should be provided as soon as possible. 
All SAEs will be followed until satisfactory resolution or until the PI or sub-investigator deems 
the event to be chronic or the subject to be stable. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
The null hypothesis corresponding to the primary analysis of this study is: 
H0: The sum of the probability that a subject assigned to the 5-day arm will have a higher DOOR 
than if assigned to the 10-day arm plus one-half the probability of equal DOORs is 50% (i.e., no 
difference in DOOR). 
The primary study sample size is based on a superiority test of the null hypothesis above, under 
an assumed alternative hypothesis that the sum of the probability that a subject assigned to the 5-
day arm will have a higher DOOR than if assigned to the 10-day arm plus one-half the 
probability of equal DOORs is 60% (p=60%). 
A sample size of 360 (180 per arm) provides 90% power using a 2-sided alpha=0.05 with a 
Wilcoxon Mann-Whitney U test (see calculation below). If p=65% or 70%, then a total sample 
size of 160 (80 per arm) or 90 (45 per arm), respectively, would be required. The sample size is 
inflated by ~10% based on an estimate from a similar study, in order to account for loss to 
follow-up resulting in a total sample size of 400 (200/arm). 
Sample size calculations were based on the formula below (Noether 1987): 
 
𝑁𝑁=
൫𝑧𝑧𝛼𝛼+ 𝑧𝑧𝛽𝛽൯
2
12𝑐𝑐(1 −𝑐𝑐) ቀ𝑝𝑝′′ −1
2ቁ
2 
𝑧𝑧𝛼𝛼= Φ−1(0.975); 𝑧𝑧𝛽𝛽= Φ−1(0.90); (90% power for two-sided test with 5% Type I error) 
𝑐𝑐= 0.5 (equal allocation to treatment arms) 
𝑝𝑝′′ = 0.6 (Pr(Higher DOOR) under alternative hypothesis) 
Note that the primary analysis statistical methods use the ITT analysis population and will 
account for missing data with multiple imputation. The exact analysis method was not used for 
the power calculation because it would require an excessive amount of assumptions about the 
nature and patterns of missing data in the final dataset and relationships of components of the 
imputation model to the primary outcome. Instead, a complete case analysis assuming 90% 
evaluable for analysis was used to obtain approximately 90% power in the actual analysis. 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
All continuous variables will be summarized using the following descriptive statistics: n (non-
missing sample size), mean, standard deviation, median, maximum and minimum. The frequency 
and percentages (based on the non-missing sample size) of observed levels will be reported for 
all categorical measures. In general, all data will be listed, sorted by site, treatment and subject, 
and when appropriate by visit number within subject. All summary tables will be structured with 
a column for each treatment and will be annotated with the total population size relevant to that 
table/treatment, including any missing observations. 
6.2. 
Timing of Analyses 
One interim analysis will be performed and reported to the data and safety monitoring board 
(DSMB) after approximately 30% of the targeted subjects have completed the study. The interim 
analysis will inform DSMB decisions regarding stopping early for efficacy, futility, or safety. 
The final analysis will be performed after database lock. Specific tables and figures may be 
released after DMID approval prior to CSR completion. 
6.3. 
Analysis Populations 
The primary analysis will be performed using the intention-to-treat (ITT) cohort. Other analyses, 
as specified below, may use complete case (CC) or according-to-protocol (ATP) cohorts. 
Analyses of the ITT cohort will include imputation for missing data, while analyses of CC and 
ATP cohorts will not contain missing data by design, because they are required to have sufficient 
data to define unambiguously the Outcome Assessment Visit #1 DOOR or Outcome Assessment 
Visit #2 DOOR. 
Reasons for exclusion from each analysis population are summarized in Table 5 and shown by 
subject in Listing 4. Excluded subjects might satisfy multiple criteria justifying their exclusion, 
but will have only one reason indicated in Table 5 and Listing 4. The reason indicated will be 
determined by the following rules. 
ITT Exclusions 
• 
Subject became ineligible before taking study product. 
CC-V1 Exclusions 
• 
Subject not treated with study product 
• 
Not excluded for any reason above, but early termination before Outcome Assessment 
Visit #1 (subjects will be tabulated by reason for termination) 
• 
Not excluded for any reason above, missing DOOR at Outcome Assessment Visit #1 
component: Adequate Clinical Response 
• 
Not excluded for any reason above, missing DOOR at Outcome Assessment Visit #1 
component: Resolution of Symptoms 


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• 
Not excluded for any reason above, missing DOOR at Outcome Assessment Visit #1 
component: Solicited Event Severity Days 1-5 
• 
Not excluded for any reason above, missing DOOR at Outcome Assessment Visit #1 
component: Number of Days of Antibiotic Use 
CC-V2 Exclusions 
• 
Subject not treated with study product 
• 
Not excluded for any reason above, but early termination before Outcome Assessment 
Visit #2 (subjects will be tabulated by reason for termination) 
• 
Not excluded for any reason above, missing DOOR at Outcome Assessment Visit #2 
component: Adequate Clinical Response 
• 
Not excluded for any reason above, missing DOOR at Outcome Assessment Visit #2 
component: Resolution of Symptoms 
• 
Not excluded for any reason above, missing DOOR at Outcome Assessment Visit #2 
component: Solicited Event Severity Days 1-18 
• 
Not excluded for any reason above, missing DOOR at Outcome Assessment Visit #2 
component: Number of Days of Antibiotic Use 
ATP-V1 Exclusion Reasons 
• 
The subject was excluded from CC-V1 cohort 
• 
Not excluded for any reason above, subject did not receive at least one dose of study 
product each day from Day 1 to Day 5 
• 
Not excluded for any reason above, major protocol deviation (see Section 6.3.3; subjects 
will be tabulated by type of protocol deviation) 
• 
Outcome Assessment Visit #1 occurred out of the protocol defined window of Day 6-10 
• 
Outcome Assessment Visit #1 did not occur as an in-person visit 
ATP-V2 Exclusion Reasons 
• 
The subject was excluded from CC-V2 cohort 
• 
Not excluded for any reason above, subject did not receive at least one dose of study 
product each day from Day 1 to Day 5 
• 
Not excluded for any reason above, major protocol deviation (see Section 6.3.3, subjects 
will be tabulated by type of protocol deviation) 
• 
Outcome Assessment Visit #2 occurred out of the protocol defined window of Day 19-25 
• 
Outcome Assessment Visit #2 did not occur as an in-person visit 
6.3.1. 
Intention-to-Treat Analysis (ITT) Cohort 
The ITT cohort will include all randomized subjects that were still eligible on Day 1 of the study. 
The analyses on the ITT cohort will be performed per randomized treatment assignment. 


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Randomized subjects who became ineligible before Day 1 of the study and did not take any 
study product will be excluded from ITT. Subjects randomized but not treated for other reasons 
other than ineligibility will be analyzed in the ITT cohort, but will have adequate clinical 
response and its components treated as missing. Therefore, in ITT analyses, OCR and DOOR 
will be missing and will need to be imputed for subjects that were not treated. If data (solicited 
events, cough, etc.) are collected post-randomization for a subject that was not treated, that data 
will be used in the ITT analysis to assist in imputing the OCR and DOOR. 
6.3.2. 
Complete Case (CC) Cohorts 
Subjects in a CC analysis are analyzed as randomized but excluded from analysis if missing data 
prevents assigning an unambiguous value to the DOOR endpoint or if the subject has not 
received at least one dose of study product. The CC-V1 cohort will consist of all subjects with 
sufficient data to define unambiguously the Outcome Assessment Visit #1 DOOR. The CC-V2 
cohort will consist of all subjects with sufficient data to define unambiguously the Outcome 
Assessment Visit #2 DOOR. 
6.3.3. 
According-to-Protocol (ATP) Cohorts 
Subjects in an ATP analysis require no major protocol deviations, and recorded receipt of at least 
one dose of study product each day from Day 1 to Day 5. What constitutes a major protocol 
deviation will be assessed on a case-by-case basis by a DMID/VTEU/ARLG committee prior to 
any member of the committee being unblinded to treatment assignments.  Subjects in an ATP 
analysis will be analyzed as treated. The ATP-V1 cohort will restrict subjects to those in CC-V1 
that furthermore meet the ATP requirements. The ATP-V2 cohort will restrict subjects to those 
in CC-V2 that furthermore meet the ATP requirements. 
6.3.4. 
Safety Analysis Population 
The safety analysis population will consist of all subjects with recorded receipt of any amount of 
study product. The analyses on the safety analysis population will be performed per treatment 
actually received. 
6.4. 
Covariates and Subgroups 
Subjects will be recruited from multiple clinical sites, but randomization will not be stratified by 
site. Randomization will use a total of 12 strata, with stratification by 1) age group (<24 months 
vs. 24-71 months), 2) initially prescribed antibiotic (amoxicillin vs. amoxicillin-clavulanate vs. 
cefdinir), and 3) treatment site (emergency department vs. outpatient clinic/urgent care facility). 
6.5. 
Missing Data 
While all efforts will be made to minimize missing data, some missing data is expected. 
Whenever possible, subjects terminating from the study early will be given an early termination 
visit during which the available components of the DOOR and related measures can be recorded. 
The primary analysis will use multiple imputation with linear models to impute values using 
available information (treatment, randomization strata variables, and available visit information), 
assuming a missing at random (MAR) model. Secondary analyses will further examine the 
robustness of this analysis, including a “worst case analysis” in which all imputations of missing 


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data will be the worst case (result in the lowest possible DOOR given available information) for 
subjects in the 5-day arm and best case for subjects in the 10-day arm. Day 1 in this study is 
defined as the date of first receipt of study product. If a subject has no record of study product 
administration or did not receive a first dose of study product, but has other post-randomization 
data, Day 1 will be imputed as the date 5 days after the date of first receipt of initial antibiotic. 
In some cases, a subject may have DOOR defined despite missing some of its components, in 
which case the subject will be eligible for inclusion into the CC and ATP analysis populations. In 
analyses of the components of the DOOR using the CC and ATP analysis populations, data will 
be analyzed as available and missing data will not be imputed. 
The study includes several composite variables with rules for assignment, missingness, and 
imputation described below. 
6.5.1. 
Adequate Clinical Response to OAV#1 or OAV#2 
Subjects that have no record of receipt of at least one dose of study product will have adequate 
clinical response and its components considered missing at both OAV#1 and OAV#2. Otherwise, 
if a subject dies at any point during subject participation in the study, the subject will be 
considered as not having adequate clinical response at OAV#1 or OAV#2. Otherwise, if a 
subject does not have OAV#1 then ACR and its components are missing for OAV#1 and if a 
subject does not have OAV#2 then ACR and its components are missing for OAV#2. 
Several variables are used to define the Adequate Clinical Response: 
• 
MAVABRX: Was the subject prescribed or did the subject receive an additional 
antibiotic treatment at this visit? (Yes/No) 
o MAVABCP: If Yes, was the antibiotic given for pneumonia or treatment for a 
complication of pneumonia? (Yes/No) 
• 
MAVPLEUR: Drainage of pleural fluid as treatment for pneumonia or a complication of 
pneumonia? (Yes/No) 
• 
MAVCHTB: Placement of a chest tube as treatment for pneumonia or a complication of 
pneumonia? (Yes/No) 
• 
MAVVIDEO: Video assisted thoracoscopic surgery as treatment for pneumonia or a 
complication of pneumonia? (Yes/No) 
• 
MAVTHOR: Thoracotomy procedure as treatment for pneumonia or a complication of 
pneumonia? (Yes/No) 
• 
MAVSURG: Any other surgical procedure as treatment for pneumonia or a complication 
of pneumonia? (Yes/No) 
• 
MAVHOSP: Was the subject hospitalized at this visit? (Yes/No) 
o MAVHPPN: If Yes, was the hospitalization for the treatment of pneumonia or 
pneumonia complications? (Yes/No) 
If a subject has OAV#1 and did not have a medically attended visit (MAV) from Day 1 to Day 5, 
inclusive, then the subject had adequate clinical response for OAV#1. If the subject had a MAV 
from Day 1 to Day 5 for which MAVABRX and MAVABCP were both YES (receipt of a non-


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study systemic antibiotic for pneumonia), or for which MAVPLEUR, MAVCHTB, 
MAVVIDEO, MAVTHOR, or MAVSURG were YES (treatment for a complication of 
pneumonia, including drainage of pleural fluid, placement of a chest tube, video assisted 
thoracoscopic surgery, or thoracotomy procedures), then the subject did not have adequate 
clinical response at OAV#1. If the subject had a MAV from Day 1 to Day 5 for which 
MAVHOSP and MAVHPPN were both YES (subject was hospitalized for the treatment of 
pneumonia or pneumonia complications), then the subject did not have adequate clinical 
response at OAV#1. Otherwise, if the subject had a MAV from Day 1 to Day 5 and either 
MAVABRX was missing, MAVABRX was YES and MAVABCP was missing, or any of 
MAVPLEUR, MAVCHTB, MAVVIDEO, MAVTHOR, or MAVSURG were missing, then 
adequate clinical response at OAV#1 is missing. Otherwise, if a subject has one or more MAVs 
from Day 1 to Day 5, with no MAV indicating receipt of a non-study systemic antibiotic for 
pneumonia or treatment for a complication of pneumonia, including drainage of pleural fluid, 
placement of a chest tube, video assisted thoracoscopic surgery, or thoracotomy procedures and 
no hospitalization for treatment of pneumonia or pneumonia complications and no MAV missing 
data as described, then the subject has adequate clinical response at OAV#1. Note that for 
determining whether the medical treatment or hospitalization falls within the period of Day 1 to 
Day 5, the date of the initial MAV will be used (MAVVISDT), rather than specific dates of 
surgery or hospitalization entered on the MAV form. 
If a subject has OAV#2 and did not have a medically attended visit (MAV) from Day 1 to Day 
18, inclusive, then the subject had adequate clinical response for OAV#2. If the subject had a 
MAV from Day 1 to Day 18 for which MAVABRX and MAVABCP were both YES (receipt of 
a non-study systemic antibiotic for pneumonia), or for which MAVPLEUR, MAVCHTB, 
MAVVIDEO, MAVTHOR, or MAVSURG were YES (treatment for a complication of 
pneumonia, including drainage of pleural fluid, placement of a chest tube, video assisted 
thoracoscopic surgery, or thoracotomy procedures), then the subject did not have adequate 
clinical response at OAV#2. If the subject had a MAV from Day 1 to Day 18 for which 
MAVHOSP and MAVHPPN were both YES (subject was hospitalized for the treatment of 
pneumonia or pneumonia complications), then the subject did not have adequate clinical 
response at OAV#2. Otherwise, if the subject had a MAV from Day 1 to Day 18 and either 
MAVABRX was missing, MAVABRX was YES and MAVABCP was missing, or any of 
MAVPLEUR, MAVCHTB, MAVVIDEO, MAVTHOR, or MAVSURG were missing, then 
adequate clinical response at OAV#2 is missing. Otherwise, if a subject has one or more MAVs 
from Day 1 to Day 18, with no MAV indicating receipt of a non-study systemic antibiotic for 
pneumonia or treatment for a complication of pneumonia, including drainage of pleural fluid, 
placement of a chest tube, video assisted thoracoscopic surgery, or thoracotomy procedures and 
no hospitalization for treatment of pneumonia or pneumonia complications and no MAV missing 
data as described, then the subject has adequate clinical response at OAV#2. Note that for 
determining whether the medical treatment or hospitalization falls within the period of Day 1 to 
Day 18, the date of the initial MAV will be used (MAVVISDT), rather than specific dates of 
surgery or hospitalization entered on the MAV form. 
The below pseudocode summarizes the logic for defining ACR at OAV#1. 
if no recorded receipt of study product then ACR_OAV1=missing 
else if death then ACR_OAV1=NO 


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else if subject does not have OAV#1 then ACR_OAV1=missing 
else if subject has no MAV from Day 1 to Day 5 then ACR_OAV1=YES 
else if subject has one or more MAVs from Day 1 to Day 5 with 
(MAVABRX=YES and MAVABCP=YES) or  
MAVPLEUR=YES or  
MAVCHTB=YES or  
MAVVIDEO=YES or  
MAVTHOR=YES or  
MAVSURG=YES or 
(MAVHOSP=YES and MAVHPPN=YES) 
then ACR_OAV1=NO 
else if subject has MAV from Day 1 to Day 5 with  
MAVABRX=missing or  
(MAVABRX=YES and MAVABCP=missing) or  
MAVPLEUR= missing or 
MAVCHTB= missing or 
MAVVIDEO= missing or 
MAVTHOR= missing or  
MAVSURG= missing  
then ACR_OAV1=missing 
else ACR_OAV1=YES 
6.5.2. 
Fever at OAV#1 or OAV#2 
Two variables are used to define Fever at OAV#1 or OAV#2: 
• 
ACRTEMP: Has the subject had a recorded temperature > 38.3 °C (100.9 °F) in the past 
24 hours? (Yes/No) 
• 
ACRFEV: If Yes, was fever attributed to a process unrelated to the prior diagnosis of 
pneumonia? (Yes/No) 
Fever at Outcome Assessment Visit #1 and Fever at Outcome Assessment Visit #2 both involve 
several data components and have complex rules for when they are considered missing versus 
when fever is considered present or not present. The below logic describes the rules. Note that 
“fever is observed as a solicited event” only if a temperature of ≥ 38.3 °C (100.9 °F) was 
recorded on the day of the Outcome Assessment Visit or on the day prior to the Outcome 
Assessment Visit and either had no recorded confirmatory measurement at least 15 minutes after 
the first measurement or else the confirmatory measurement also indicated a temperature of ≥ 
38.3 °C (100.9 °F). Fever at the OAV is never missing if the OAV did occur (specifically, 
ACRTEMP not missing), and the vital signs measurement at the visit and the actual temperatures 
reported by parents and recorded on the solicited events form (SRS) are treated as optional and 
supplemental data in the determination of the presence of fever at the visit. 
• 
If the OAV did occur 
o If subject had a recorded temperature ≥ 38.3 °C (100.9 °F) (ACRTEMP) and fever is 
not indicated as unrelated to prior diagnoses of pneumonia (ACRFEV), then fever at 
the OAV is present 


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o If subject had a recorded temperature ≥ 38.3 °C (100.9 °F) (ACRTEMP) and fever is 
indicated as unrelated to prior diagnoses of pneumonia (ACRFEV), then fever at the 
OAV is absent  
o If subject had a recorded temperature ≥ 38.3 °C (100.9 °F) (ACRTEMP) and fever is 
indicated as relatedness to prior diagnoses of pneumonia (ACRFEV) is missing, then 
fever at the OAV is missing 
o If subject had a recorded temperature < 38.3 °C (100.9 °F) (ACRTEMP), then fever 
at the OAV is absent 
6.5.3. 
Resolution of Symptoms at OAV#1 or OAV#2 
Resolution of symptoms is defined as the absence of all of the following: 
• 
Fever at the OAV, as defined above 
• 
Elevated respiratory rate (RR >50 breaths/minute for children <24 months of age and >40 
breaths/minute for children 24-71 months of age) at the time of the Outcome Assessment 
Visit (VS1.RESPB); 
• 
Presence of cough grade 2 or 3 at the Outcome Assessment Visit (ACRCGHSV) 
If the subject died at any point of participation in the study, then the subject will be analyzed as 
not having resolution of symptoms at either Outcome Assessment Visit. Otherwise, if the subject 
did not have adequate clinical response at OAV#1 or OAV#2, then the subject will be analyzed 
as not having resolution of symptoms at the respective Outcome Assessment Visit(s). Otherwise, 
if fever, elevated respiratory rate, or presence of grade 2 or 3 cough is indicated at OAV#1 or 
OAV#2, then the subject does not have resolution of symptoms at the respective Outcome 
Assessment Visit (regardless of whether some components of the resolution of symptoms are 
missing). Otherwise, if fever, respiratory rate, and presence of cough are all non-missing and are 
indicated as 'No' at OAV#1 or OAV#2, then the subject has resolution of symptoms at the 
respective Outcome Assessment Visit. Otherwise, resolution of symptoms is missing at the 
Outcome Assessment Visit. 
6.5.4. 
Most Severe Solicited Event at OAV#1 and OAV#2 
The maximum severity at OAV #1 will be calculated based on the following rules: 
• If a subject has missing data for the severity grade of any solicited event for two 
consecutive days or has missing data for more than two days from Day 1 to Day 5 then 
the most severe solicited event at OAV#1 will be missing.  
• Otherwise if a subject has missing data for one or two non-consecutive days from Day 1 
to Day 5 then the missing severity will be imputed as the maximum severity grade taken 
across the previous day and the day after the day with a missing severity. As a special 
case, for subjects missing severity for Day 1, the missing severity will be imputed as the 
Severity from Day 2. For subjects missing severity at Day 5 but not missing severity at 
Day 6, the missing severity will be imputed as the maximum of severity gradings from 
Day 4 and Day 6. For these subjects with severity grades (0 to 3) recorded or imputed for 
every solicited event (irritability, vomiting, diarrhea, allergic reaction, stomatitis, and 
candidiasis) from Day 1 to Day 5, inclusive, the most severe solicited event at OAV#1 


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will be the maximum severity grade taken across all solicited events from Day 1 to Day 
5. 
•  If a subject had any solicited event of severity grade 3 from Day 1 to Day 5, then the 
most severe solicited event at OAV#1 will be grade 3, regardless of the presence of 
missing data during that period. 
In a similar manner, the maximum severity at OAV #2 will be calculated based on the following 
rules: 
• If a subject has missing data for the severity grade of any solicited event for more than 
three consecutive days or has missing data for more than five days from Day 1 to Day 18 
then the most severe solicited event at OAV#2 will be missing. 
• Otherwise if a subject has missing data for five days or less and no more than three of 
them are consecutive   Day 1 to Day 18 then the missing severity will be imputed as the 
maximum severity grade taken across the previous day and the day after the day with a 
missing severity. As a special case, for subjects missing severity for Day 1, the missing 
severity will be imputed as the Severity from Day 2. For subjects missing severity at Day 
18, the missing severity will be imputed as the severity from Day 17. For these subjects 
with severity grades (0 to 3) recorded or imputed for every solicited event (irritability, 
vomiting, diarrhea, allergic reaction, stomatitis, and candidiasis) from Day 1 to Day 18, 
inclusive, the most severe solicited event at OAV#2 will be the maximum severity grade 
taken across all solicited events from Day 1 to Day 18. 
•  If a subject had any solicited event of severity grade 3 from Day 1 to Day 18, then the 
most severe solicited event at OAV#2 will be grade 3, regardless of the presence of 
missing data during that period. 
6.5.5. 
Ordinal Clinical Response at OAV#1 or OAV#2 
If the subject died at any point of study participation, then OCR at OAV#1 will be 8. 
Else if the subject has missing ACR at OAV#1 then OCR at OAV#1 will be missing. 
Else if the subject did not have ACR at OAV#1 and was hospitalized from Day 1 to Day 5 then 
OCR at OAV#1 will be 7. 
Else if the subject did not have ACR at OAV#1 and was not hospitalized from Day 1 to Day 5 
then OCR at OAV#1 will be 6. 
Else if the subject has missing resolution of symptoms at OAV#1 then OCR at OAV#1 will be 
missing. 
Else if the subject did not have resolution of symptoms at OAV#1 then OCR at OAV#1 will be 
5. 
Else if the subject has missing most severe solicited event at OAV#1 then OCR at OAV#1 will 
be missing. 
Else if the subject had a most severe solicited event of grade 3 at OAV#1 then OCR at OAV#1 
will be 4. 


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Else if the subject had a most severe solicited event of grade 2 at OAV#1 then OCR at OAV#1 
will be 3. 
Else if the subject had a most severe solicited event of grade 1 at OAV#1 then OCR at OAV#1 
will be 2. 
Else OCR at OAV#1 will be 1. 
If the subject died at any point of study participation, then OCR at OAV#2 will be 8. 
Else if the subject has missing ACR at OAV#2 then OCR at OAV#2 will be missing. 
Else if the subject did not have ACR at OAV#2 and was hospitalized from Day 1 to Day 18 then 
OCR at OAV#2 will be 7. 
Else if the subject did not have ACR at OAV#2 and was not hospitalized from Day 1 to Day 18 
then OCR at OAV#2 will be 6. 
Else if the subject has missing resolution of symptoms at OAV#2 then OCR at OAV#2 will be 
missing. 
Else if the subject did not have resolution of symptoms at OAV#2 then OCR at OAV#2 will be 
5. 
Else if the subject has missing most severe solicited event at OAV#2 then OCR at OAV#2 will 
be missing. 
Else if the subject had a most severe solicited event of grade 3 at OAV#2 then OCR at OAV#2 
will be 4. 
Else if the subject had a most severe solicited event of grade 2 at OAV#2 then OCR at OAV#2 
will be 3. 
Else if the subject had a most severe solicited event of grade 1 at OAV#2 then OCR at OAV#2 
will be 2. 
Else OCR at OAV#2 will be 1. 
Note that in some cases OCR can be defined even if some components are missing. For instance, 
if a subject had record of receipt of study product and did not have adequate clinical response at 
OAV#1, OCR at OAV#1 would still be defined even if most severe solicited event at OAV#1 
was missing. 
6.5.6. 
Number of Days of Antibiotic Use at OAV#1 or OAV#2 
It will be assumed that all subjects have precisely five days of antibiotic use with the initial 
antibiotic prior to Day 1 (the day of the first dose of study product). Analysis involving 
comparisons of the number of days of antibiotic use will consider antibiotic use from Day 1 
onwards. The number of days of antibiotic use is defined as the actual number of days of 
antibiotic use (any amount of study product that is not placebo, or any amount of other systemic 
antibiotic) from Day 1 to Day 5, inclusive, for OAV#1 and from Day 1 to Day 18 for OAV#2. 
For subjects that received placebo as study product, it is counted as the number of days of 
systemic antibiotic as determined solely from the concomitant medication form. For subjects that 
receive actual antibiotic as study product, it is counted as the number of days that the subject 
received any amount of either study product or a non-study systemic antibiotic, as determined 


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from the concomitant medication form. Note that missed doses of study product do not 
necessarily lower the number of days of antibiotic use as long as a separate dose of antibiotic 
(study product antibiotic or concomitant medication antibiotic) was received on that day. Extra 
doses of study product beyond the protocol specification of 10 doses count as normal toward the 
number of days of antibiotic use. The number of days of antibiotic use is missing (at both 
OAV#1 and OAV#2) if the product administration record was not completed / on record for the 
subject and the subject did not have antibiotic use during the study period recorded as a 
concomitant medication. If a subject does not have an OAV#1 or OAV#2, then number of days 
of antibiotic use at OAV#1 is missing. If a subject does not have an OAV#2, then number of 
days of antibiotic use at OAV#2 is missing. As exceptions, subjects that were hospitalized due to 
pneumonia or a complication of pneumonia or the died during the study period will have number 
of days of antibiotic use at OAV#1 or OAV#2 as 5 if randomized to the standard course or as 0 if 
randomized to short course if the number of days of antibiotic use at OAV#1 or OAV#2 is 
missing as defined above. 
The number of days of antibiotic use at the time of analysis will be determined from the product 
administration records and concomitant medication records only. Data management activities 
and site queries (outside the scope of this document) prior to data lock will ensure concomitant 
medication records are as complete as possible and consistent with other records (i.e., AEs and 
medically attended visit records in the clinical database). The number of days of antibiotic use 
for a concomitant medication will be calculated as the medication end date minus the medication 
start date plus one day. Days will not be double counted if multiple systemic antibiotics 
(including antibiotic as study product) are taken on the same day. Systemic antibiotic use will not 
be counted for days that fall outside of the range being considered (Days 1 to Day 5, or Day 1 to 
Day 18). 
If there is a start date but not an end date for a concomitant medication in the clinical database, 
then the end date for analysis will be imputed as follows. If the subject completed the study, then 
the end date for analysis will be reported as the protocol completion date. If the subject 
terminated early from the protocol and there is at least one other record for the same antibiotic in 
the concomitant medications records with start and end date known (record may belong to any 
subject), the end date of treatment for that antibiotic will be imputed by adding the mean 
observed number of days of treatment rounded up to the nearest integer for that antibiotic (minus 
1). If no such records exist for the antibiotic and the subject terminated early, the end date of 
treatment for that antibiotic will be imputed by adding to the start date the mean observed 
number of days of treatment rounded up to the nearest integer for all systemic antibiotics in the 
concomitant medication records (minus 1). 
6.5.7. 
Desirability of Outcome Ranking (DOOR) at OAV#1 or OAV#2 
DOOR at OAV#1 is defined by ranking all subjects (pooling together both treatment arms) 
according to OCR at OAV#1 (lower is better) and using the number of days of antibiotic use at 
OAV#1 (lower is better) as a tie-breaker for comparing the ranking of two subjects with the same 
OCR. DOOR at OAV#2 is defined by ranking all subjects (pooling together both treatment arms) 
according to OCR at OAV#2 (lower is better) and using the number of days of antibiotic use at 
OAV#2 (lower is better) as a tie-breaker for comparing the ranking of two subjects with the same 
OCR. DOOR at OAV#1 or at OAV#2 is missing only if OCR or number of days of antibiotic use 
is missing for the respective OAV. 


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The ranking algorithm for DOOR is implemented as follows. A score variable is created that 
adds the number of days of antibiotic use (as defined in Section 6.5.6) divided by 100 to the 
OCR. Subjects are then ranked (DOOR) by the score, with the highest rank going to the subject 
with the lowest score, and the lowest rank going to the subject with the highest score. Tied scores 
result in a DOOR equal to the mean of the tied ranks. The algorithm is exemplified below using 
a simple scenario with 4 subjects. 
Suppose Subject A has an OCR of 1 and 5 days of antibiotic use in the study period 
(score=1.05), Subject B has an OCR of 1 and 0 days of antibiotic use (score=1.00), Subject C has 
an OCR of 2 and 0 days of antibiotic use (score=2.00), and Subject D has an OCR of 1 and 5 
days of antibiotic use (score=1.05). Because Subject B has the lowest score, Subject B is given 
DOOR=1 (the highest rank). Because Subject A and Subject D tie for the next lowest score, they 
both receive the mean of the next 2 available ranks (2 and 3, which has mean 2.5), and so the 
DOOR for both Subject A and Subject D is 2.5. Finally, Subject C has the highest score and 
therefore receives the worst available rank, which is DOOR=4. 
6.6. 
Interim Analyses and Data Monitoring 
One interim analysis, described below, will be performed by the SDCC statistician responsible 
for this protocol and reported to the DSMB after approximately 30% of the targeted subjects 
have completed the study. The interim analysis will inform DSMB decisions regarding stopping 
early for efficacy, futility, or safety. Only the SDCC statistician and the DSMB will see the 
interim analysis report. 
For the interim analysis, a snapshot of the study database will be unblinded and used to conduct 
analyses as follows. An ITT analysis including all enrolled subjects in the snapshot of the study 
database will be performed, testing the null hypothesis (H0: Probability of higher DOOR in short 
course + ½ probability of equal DOOR = 0.5) using the methods described in Section 8.1.1, with 
the modification that the Haybittle-Peto boundary (p<0.001) will be used when concluding 
statistical significance. The study may be stopped early for efficacy only if statistical significance 
is detected in that test. In the event of statistical significance, sensitivity analyses using complete 
case and according-to-protocol cohorts (CC-V1 and ATP-V1, as described below) as well as 
worst case analyses will be included in the DSMB report to further guide decisions for stopping 
for efficacy. 
A 95% confidence interval for the probability that a randomly selected subject will have a better 
DOOR if assigned to the 5-day strategy (vs. the standard strategy) will be estimated but not used 
to inform DSMB decisions about stopping early for efficacy. Predicted interval plots (PIPS, 
Section 6.6.1) will be constructed to provide the DSMB with a prediction of the trial results were 
the trial to continue as planned under varying assumptions regarding future data (e.g., current 
trend continues, null hypothesis is true, alternative hypothesis is true). In order to assess whether 
the 5-day strategy is differentially effective in subgroups of subjects, 95% confidence intervals 
for the probability of higher DOOR (as well as p-values for the test of a probability of higher 
DOOR of 0.5) when assigned to the  short course of antibiotics will be shown as forest plots 
comparing each stratification variable (age <2 years, age ≥2 years, ED as the initial treatment 
site, out-patient or urgent care as the initial treatment site, amoxicillin as the initial antibiotic, 
amoxicillin-clavulanate as initial antibiotic, and cefdinir as initial antibiotic). 
The DSMB will also be provided with the following: 


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1. For subjects that have completed Outcome Assessment Visit #1 and have received at 
least one dose of study product, a between arm difference in the overall outcome 
(DOOR) via a cumulative difference plot with respective confidence bands for Outcome 
Assessment Visit #1. 
2. For subjects that have completed Outcome Assessment Visit #1 and have received at 
least one dose of study product, a forest plot of 95% confidence intervals for the risk 
difference of adequate clinical response as well as the following interventions for 
persistent or worsening pneumonia: (1) ED/clinic visits, (2) hospitalizations, (3) surgical 
procedures, and (4) non-study systemic antibiotics at Outcome Assessment Visit #1. 
3. For subjects that have completed Outcome Assessment Visit #1 and have received at 
least one dose of study product, a forest plot of 95% confidence intervals for the risk 
difference of lack of resolution of symptoms as well as the following: (1) Oral, rectal, 
axillary or tympanic temperature ≥38.3˚C (100.9˚F), confirmed by repeat measurement 
after at least 15 minutes, in the 24 hours preceding Outcome Assessment Visit #1 or 
measured at the assessment visit, unless attributed to a new process that is unrelated to 
the prior diagnosis of pneumonia; (2) Elevated respiratory rate (RR >50 breaths/minute 
for children <24 months of age and >40 breaths/minute for children 24-71 months of age) 
at Outcome Assessment Visit #1, and (3) Presence of cough Grade 2 or 3 at Outcome 
Assessment Visit #1. 
4. For subjects that have completed Outcome Assessment Visit #1 and have received at 
least one dose of study product, a forest plot of 95% confidence intervals for the risk 
difference of each solicited event and with the risk difference of any solicited event, for 
each severity threshold (mild or greater, moderate or greater, or severe) for Outcome 
Assessment Visit #1. 
The Newcombe method with continuity correction will be used to compute all 95% confidence 
intervals for risk differences. 
6.6.1. 
Predicted Interval Plots (PIPs) 
PIPs provide insight into the range of possible outcomes that can be expected for the final 
primary analysis under various assumptions (such as that the current observed treatment effect 
represents the true effect or that the null hypothesis represents the true effect). Using various 
assumptions, data is simulated from theoretical distributions to create multiple complete datasets 
representing complete datasets for the final analysis under the assumed reality. Details of PIPs 
and their interpretations can be found in the literature (Evans 2007, Li 2009). 
For each assumption, one-hundred (100) 95% predicted intervals of the probability of higher 
DOOR in the 5-day treatment course at Outcome Assessment Visit #1 will be generated from 
100 complete datasets. Each dataset will include the ITT analysis population for the interim 
analysis, plus additional simulated subjects to a total of 400 subjects in the dataset. Predicted 
intervals will be computed by inverting the Mann-Whitney U test (Section 8.2.2). The predicted 
intervals will be ordered by their corresponding point estimate of the probability of higher 
DOOR in the 5-day treatment course and shown graphically as forest plots. The 95% confidence 
interval generated in the ITT interim analysis of the probability of higher DOOR at Outcome 
Assessment Visit #1 will be overlaid on the forest plot. Comparisons of the predicted intervals to 


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the confidence interval show changes in precision of estimated probability (tightness of predicted 
intervals versus the confidence interval) as well as the expected distribution of location shifts of 
the estimated probability in the final analysis relative to the interim analysis, dependent on the 
assumptions used. Conditional power will be estimated as the percentage of predicted intervals 
with a lower bound that is greater than 0.5. 
Three assumptions will be included in the PIPs: 1) current trend, 2) null hypothesis, and 3) 
alternative hypothesis. Further assumptions may be explored depending on results of the ITT 
analysis of the primary endpoint but will not be pre-specified. 
Under the current trend assumption, each complete dataset is simulated in the following way. 
Multiple imputation will be used (Section 8.4.1) to create 100 datasets with complete data for 
DOOR at Outcome Assessment Visit #1 for enrolled subjects. For each of these 100 datasets, 
future subjects will be added to the analysis dataset. The number of future subjects added will be 
chosen to bring the total number of subjects (real and simulated combined) to 400 in the analysis 
dataset. The treatment ratio in the simulated subjects will be 1:1. The DOOR values for the 
future subjects in each dataset will be simulated by sampling with replacement from the 
empirical distribution of DOOR values by treatment from the same dataset. 
Under the null hypothesis assumption, each complete dataset is simulated in the following way. 
Multiple imputation will be used (Section 8.4.1) to create 100 datasets with complete data for 
DOOR at Outcome Assessment Visit #1 for enrolled subjects. For each of these 100 datasets, 
future subjects will be added to the analysis dataset. The number of future subjects added will be 
chosen to bring the total number of subjects (real and simulated combined) to 400 in the analysis 
dataset. The treatment ratio in the simulated subjects will be 1:1. The DOOR values for the 
future subjects in each dataset will be simulated by sampling with replacement from the overall 
(not by treatment) empirical distribution of DOOR values from the same dataset. 
Under the alternative hypothesis assumption, each complete dataset is simulated in the following 
way. Multiple imputation will be used (Section 8.4.1) to create 100 datasets with complete data 
for DOOR at Outcome Assessment Visit #1 for enrolled subjects. For each of these 100 datasets, 
future subjects will be added to the analysis dataset. The number of future subjects added will be 
chosen to bring the total number of subjects (real and simulated combined) to 400 in the analysis 
dataset. The treatment ratio in the simulated subjects will be 1:1. The DOOR values for the 
future subjects in each dataset will be simulated by sampling with replacement from the overall 
(not by treatment) empirical distribution of DOOR values from the same dataset. All simulated 
subjects with a treatment assignment randomly chosen as the 5-day course will have the DOOR 
(rank) shifted by a value beta. The value beta will be chosen through a manual trial-and-error 
process such that the probability of higher DOOR in the 5-day subjects, comparing simulated 
subjects only, has a mean value of approximately 0.6 across all 100 datasets. 
6.7. 
Multicenter Studies 
This is a multicenter study. Because there are twelve strata prior to considering site, further 
stratification by site would result in an excessive number of strata and so randomization is not 
stratified by site. Therefore, treatment imbalances might by chance occur within sites. 
Additionally, the potential for site effects on DOOR components is present. Therefore, 
sensitivity analyses for potential site effects are necessary. 


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In the primary analysis, data will be pooled across all clinical sites and analyses will not adjust 
for potential site effects. However, as a sensitivity analysis, the ITT analysis of DOOR at 
Outcome Assessment Visit #1 will be repeated as a stratified analysis in which each site will be 
analyzed separately (see Section 8.3.2). 
6.8. 
Multiple Comparisons/Multiplicity 
Only one hypothesis test will be performed for the primary analysis. Secondary and exploratory 
analyses will not be corrected for multiplicity. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
Reasons for screening failures will be summarized in Table 8. The completion status and reasons 
for early termination or treatment discontinuation will be summarized (Table 4 and Listing 1). A 
subject could be discontinued early due to an AE (serious or non-serious), loss to follow-up, non-
compliance with study, voluntary withdrawal by parent/guardian, withdrawal at the investigator 
request, termination of the site by the sponsor, termination of the study by the sponsor, death, 
lack of eligibility at enrollment, or becoming ineligible after enrollment. 
Subject disposition and eligibility for analysis will be summarized in a CONSORT flow diagram 
(Figure 2). 
7.2. 
Protocol Deviations 
A summary of subject-specific protocol deviations will be presented by the reason for the 
deviation, the deviation category, and treatment group for all subjects (Table 2 and Listing 2). 
Non-subject specific protocol deviations will be in Listing 3. All subject-specific protocol 
deviations and non subject-specific protocol deviations will be presented. Major protocol 
deviations (see Section 6.3.3) will be discussed. 


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8. 
EFFICACY EVALUATION 
All efficacy variables will be listed by subject. Data will be summarized by treatment group. 
Continuous efficacy variables will be summarized with the number of observations, mean, 
median standard deviation, minimum and maximum. Categorical efficacy variables will be 
summarized by number and percent in each category. 
All statistical tests are two-sided and performed at the α=0.05 significance level. 
8.1. 
Primary Efficacy Analysis 
The primary efficacy analyses will be performed for the ITT cohort. 
8.1.1. 
Primary Analysis of DOOR at Outcome Assessment Visit #1 
DOOR at Outcome Assessment Visit #1 is defined in Section 3.3. 
The null hypothesis corresponding to the primary analysis of this study is: 
H0: The sum of the probability that a subject assigned to the 5-day arm will have a higher 
DOOR at Outcome Assessment Visit #1 than if assigned to the 10-day arm plus one-half 
the probability of equal DOORs at Outcome Assessment Visit #1 is 50% (i.e., no 
difference in DOOR at Outcome Assessment Visit #1). 
The above null hypothesis can be tested using a Mann-Whitney U Test (Evans 2015). 
The primary analysis will use multiple imputation with a linear model to impute missing DOOR 
at Outcome Assessment Visit #1 outcomes. Details of multiple imputation methods are described 
in Section 8.4.1. 
For each of the 20 complete multiply imputed datasets, a Mann-Whitney U statistic will be 
computed using randomization to short course versus randomization to standard course to define 
the binary grouping and DOOR at Outcome Assessment Visit #1 as the outcome. The U statistics 
are asymptotically normal distributed, and so they can be combined into a single test statistic 
using Rubin’s Rules (Marshall 2009). 
Defining the following: 
𝑛𝑛1: number of subjects in ITT cohort randomized to a short course of antibiotics 
𝑛𝑛2: number of subjects in ITT cohort randomized to a standard course of antibiotics 
𝑚𝑚: number of imputed datasets (𝑚𝑚= 20) 
𝑄𝑄𝑖𝑖: U statistic computed from the ith multiply imputed dataset 
𝑄𝑄ത=
1
𝑚𝑚∑
𝑄𝑄𝑖𝑖
𝑚𝑚
𝑖𝑖=1
  
𝑄𝑄0: the expected value of a U statistic under the null hypothesis   (𝑄𝑄0 =
𝑛𝑛1𝑛𝑛2
2 ) 
𝑈𝑈ഥ: The within imputation variance (this is not the mean of the U statistics). Correcting for ties, 
the formula for the within imputation variance of U is: 
𝑈𝑈ഥ= Var(𝑄𝑄𝑖𝑖) = 𝑛𝑛1𝑛𝑛2
12 ൤(𝑛𝑛1 + 𝑛𝑛2 + 1) −෍
(𝑀𝑀𝑐𝑐
3 −𝑀𝑀𝑐𝑐)
𝐷𝐷
𝑐𝑐=1
൨       (Lehmann 1975, Zhao 2008), 


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where 𝑀𝑀𝑐𝑐 is the number of tied ranks for the 𝑐𝑐th value DOOR in the dataset and 𝐷𝐷 is the number 
of distinct values of DOOR in the dataset. Because the numbers of tied ranks should be very 
similar across the 20 multiply imputed datasets, the number of ties will be counted from the first 
imputed dataset only, and those counts will be used to compute the corrected variance. 
𝐵𝐵=
1
𝑚𝑚−1 ∑
(𝑄𝑄𝑖𝑖−𝑄𝑄ത)2
𝑚𝑚
𝑖𝑖=1
  
𝑇𝑇= 𝑈𝑈ഥ+
𝑚𝑚+1
𝑚𝑚𝐵𝐵  
𝑊𝑊= 
(𝑄𝑄ത−𝑄𝑄0)2
𝑇𝑇
  
𝑟𝑟= 
𝑚𝑚+1
𝑚𝑚
𝐵𝐵
𝑈𝑈ഥ  
𝜈𝜈= (𝑚𝑚−1) ቀ1 +
1
𝑟𝑟ቁ
2
  
Under null hypothesis corresponding to the primary analysis of this study, 
𝑊𝑊 ~ F1,𝜈𝜈 
This F-distribution is used to compute a p-value (one-sided probability) from the overall test 
statistic 𝑊𝑊. The null hypothesis will be rejected if p<0.05. 
A corresponding 95% confidence interval for 𝑈𝑈 will be computed using the overall test statistic 
𝑊𝑊 through the inversion of the F-test. Dividing the bounds of this confidence interval by 𝑛𝑛1𝑛𝑛2 
will yield the bounds for the 95% confidence interval of Pr(Higher DOOR in short course) + 0.5 
Pr(Equal DOOR in short course). Thus, the confidence interval is given by: 
95% CI: ቆ
𝑄𝑄ത−ඥ𝑇𝑇× 𝐹𝐹0.95,1,𝜈𝜈
𝑛𝑛1𝑛𝑛2
,
𝑄𝑄ത+ ඥ𝑇𝑇× 𝐹𝐹0.95,1,𝜈𝜈
𝑛𝑛1𝑛𝑛2
ቇ 
A point estimate of the probability will be obtained by dividing 𝑄𝑄ത by 𝑛𝑛1𝑛𝑛2. Results will be 
shown in Table 14. 
8.2. 
Secondary Efficacy Analyses 
8.2.1. 
Analysis of DOOR at Outcome Assessment Visit #2, Performed as ITT in an 
Analogous Manner to the Primary Analysis 
DOOR at Outcome Assessment Visit #2 is defined in Section 3.3. 
The null hypothesis corresponding to this analysis is: 
H0: The sum of the probability that a subject assigned to the 5-day arm will have a higher 
DOOR at Outcome Assessment Visit #2 than if assigned to the 10-day arm plus one-half 
the probability of equal DOORs at Outcome Assessment Visit #2 is 50% (i.e., no 
difference in DOOR at Outcome Assessment Visit #2). 
The above null hypothesis can be tested using a Mann-Whitney U Test (Evans 2015). 
This analysis will use multiple imputation with a linear model to impute missing DOOR at 
Outcome Assessment Visit #2 outcomes. Details of multiple imputation methods are described in 
Section 8.4.1. 


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For each of the 20 complete multiple imputation datasets, a Mann-Whitney U statistic will be 
computed using randomization to short course versus randomization to standard course to define 
the binary grouping and DOOR at Outcome Assessment Visit #2 as the outcome. The U statistics 
are asymptotically normal distributed, and so they can be combined into a single test statistic 
using Rubin’s Rules (Marshall 2009). 
Defining the following: 
𝑛𝑛1: number of subjects in ITT cohort randomized to a short course of antibiotics 
𝑛𝑛2: number of subjects in ITT cohort randomized to a standard course of antibiotics 
𝑚𝑚: number of imputed datasets (𝑚𝑚= 20) 
𝑄𝑄𝑖𝑖: U statistic computed from the ith multiply imputed dataset 
𝑄𝑄ത=
1
𝑚𝑚∑
𝑄𝑄𝑖𝑖
𝑚𝑚
𝑖𝑖=1
  
𝑄𝑄0: the expected value of a U statistic under the null hypothesis   (𝑄𝑄0 =
𝑛𝑛1𝑛𝑛2
2 ) 
𝑈𝑈ഥ: The within imputation variance (this is not the mean of the U statistics). Correcting for ties, 
the formula for the within imputation variance of the Mann-Whitney U statistic is: 
𝑈𝑈ഥ= Var(𝑄𝑄𝑖𝑖) = 𝑛𝑛1𝑛𝑛2
12 ൤(𝑛𝑛1 + 𝑛𝑛2 + 1) −෍
(𝑀𝑀𝑐𝑐
3 −𝑀𝑀𝑐𝑐)
𝐷𝐷
𝑐𝑐=1
൨       (Lehmann 1975, Zhao 2008), 
where 𝑀𝑀𝑐𝑐 is the number of tied ranks for the 𝑐𝑐th value DOOR in the dataset and 𝐷𝐷 is the number 
of distinct values of DOOR in the dataset. Because the numbers of tied ranks should be very 
similar across the 20 multiply imputed datasets, the number of ties will be counted from the first 
imputed dataset only, and those counts will be used to compute the corrected variance. 
𝐵𝐵=
1
𝑚𝑚−1 ∑
(𝑄𝑄𝑖𝑖−𝑄𝑄ത)2
𝑚𝑚
𝑖𝑖=1
  
𝑇𝑇= 𝑈𝑈ഥ+
𝑚𝑚+1
𝑚𝑚𝐵𝐵  
𝑊𝑊= 
(𝑄𝑄ത−𝑄𝑄0)2
𝑇𝑇
  
𝑟𝑟= 
𝑚𝑚+1
𝑚𝑚
𝐵𝐵
𝑈𝑈ഥ  
𝜈𝜈= (𝑚𝑚−1) ቀ1 +
1
𝑟𝑟ቁ
2
  
Under null hypothesis corresponding to the primary analysis of this study, 
𝑊𝑊 ~ F1,𝜈𝜈 
This F-distribution is used to compute a p-value (one-sided probability) from the overall test 
statistic 𝑊𝑊.  The null hypothesis will be rejected if p<0.05. 
A corresponding 95% confidence interval for 𝑈𝑈 will be computed using the overall test statistic 
𝑊𝑊 through the inversion of the F-test. Dividing the bounds of this confidence interval by 𝑛𝑛1𝑛𝑛2 
will yield the bounds for the 95% confidence interval of Pr(Higher DOOR in short course) + 0.5 
Pr(Equal DOOR in short course). Thus, the confidence interval is given by: 


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95% CI: ቆ
𝑄𝑄ത−ඥ𝑇𝑇× 𝐹𝐹0.95,1,𝜈𝜈
𝑛𝑛1𝑛𝑛2
,
𝑄𝑄ത+ ඥ𝑇𝑇× 𝐹𝐹0.95,1,𝜈𝜈
𝑛𝑛1𝑛𝑛2
ቇ 
A point estimate of the probability will be obtained by dividing 𝑄𝑄ത by 𝑛𝑛1𝑛𝑛2. Results will be 
shown in Table 15. 
8.2.2. 
Sensitivity Analyses for the DOOR at Outcome Assessment Visits #1 and #2 ITT 
analyses. 
In addition to the ITT analysis of the DOOR at Outcome Assessment Visits #1 and #2, analyses 
using alternative analysis populations or imputation strategies will be performed: (1) CC 
analyses. (2) ATP analyses. (3) Worst case analyses. All of these analyses will test the null 
hypotheses described in Section 8.1.1 and Section 8.2.1 using the Mann-Whitney U Test, 
estimate Pr(Higher DOOR in short course) + 0.5 Pr(Equal DOOR) using U divided by the 
number of pairwise comparisons, and will compute confidence intervals by (1) inverting the 
Mann-Whitney U Test and (2) using a non-parametric bootstrap. Results will be shown in 
Table 16 and Table 17 for Outcome Assessment Visits #1 and #2, respectively. 
Confidence intervals from inverting the Mann-Whitney U Test: 
ቌ𝑈𝑈
𝑛𝑛1𝑛𝑛2
−1.96 × ඨVar(𝑈𝑈)
(𝑛𝑛1𝑛𝑛2)2 ,
𝑈𝑈
𝑛𝑛1𝑛𝑛2
+ 1.96 × ඨVar(𝑈𝑈)
(𝑛𝑛1𝑛𝑛2)2ቍ 
Correcting for ties, the formula for the variance of U is: 
Var(𝑈𝑈) = 𝑛𝑛1𝑛𝑛2
12 ൤(𝑛𝑛1 + 𝑛𝑛2 + 1) −෍
(𝑀𝑀𝑐𝑐
3 −𝑀𝑀𝑐𝑐)
𝐷𝐷
𝑐𝑐=1
൨       (Lehmann 1975, Zhao 2008), 
where 𝑀𝑀𝑐𝑐 is the number of tied ranks for the 𝑐𝑐th value DOOR in the dataset and 𝐷𝐷 is the number 
of distinct values of DOOR in the dataset. 
Confidence intervals using a non-parametric bootstrap: 
൬𝑈𝑈0.025
𝑛𝑛1𝑛𝑛2
, 𝑈𝑈0.975
𝑛𝑛1𝑛𝑛2
൰ 
Where 𝑈𝑈0.025 and 𝑈𝑈0.975 are chosen as the 250th and 9750th values in a sorted array of 10,000 
values of Mann Whitney U statistics generated from random resampling (number of values 
sampled to generate the statistic will be equal to the number of subjects in the respective analysis 
population) of the empirical distributions of DOOR scores in each treatment arm for the given 
analysis population. 
8.2.2.1. 
Complete Case Analysis of the DOOR at Outcome Assessment Visit #1 
Analysis will be performed as described in Section 8.2.2 using the CC-V1 population. Ordinal 
clinical response values, number of days of antibiotic use, and DOOR at outcome assessment 
visit #1 of CC-V1 subjects will be presented in Listing 19. 


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8.2.2.2. 
Complete Case Analysis of the DOOR at Outcome Assessment Visit #2 
Analysis will be performed as described in Section 8.2.2 using the CC-V2 population. Ordinal 
clinical response values, number of days of antibiotic use, and DOOR at outcome assessment 
visit #2 of CC-V2 subjects will be presented in Listing 19. 
8.2.2.3. 
According-to-Protocol Analysis of the DOOR at Outcome Assessment Visit #1 
Analysis will be performed as described in Section 8.2.2 using the ATP-V1 population. 
8.2.2.4. 
According-to-Protocol Analysis of the DOOR at Outcome Assessment Visit #2 
Analysis will be performed as described in Section 8.2.2 using the ATP-V2 population. 
8.2.2.5. 
Worst Case Analysis of the DOOR at Outcome Assessment Visit #1 
Analysis will be performed as described in Section 8.2.2 using the ITT population with missing 
values imputed as follows. Subjects in the short course arm will have their ordinal clinical 
response imputed as 8 and their number of days of antibiotic use imputed if missing (see 
Section 6.5.6) as 0. As an exception, subjects in the short course arm with OCR missing for 
Outcome Assessment Visit #1 but not for Outcome Assessment Visit #2 will have the OCR for 
Outcome Assessment Visit #1 imputed as the Outcome Assessment Visit #2 value or as 5, 
whichever value is larger. Subjects in the standard course arm will have their ordinal clinical 
response imputed as the value that would occur if all missing data was benign (no additional 
solicited events / cough / fever, etc.) and their number of days of antibiotic use imputed if 
missing (see Section 6.5.6) as 5. 
8.2.2.6. 
Worst Case Analysis of the DOOR at Outcome Assessment Visit #2 
Analysis will be performed as described in Section 8.2.2 using the ITT population with missing 
values imputed as follows. Subjects in the short course arm will have their ordinal clinical 
response imputed as 8 and their number of days of antibiotic use imputed if missing (see 
Section 6.5.6 ) as 0. Subjects in the standard course arm will have their ordinal clinical response 
imputed as the value that would occur if all missing data was benign (no additional solicited 
events / cough / fever, etc.) and their number of days of antibiotic use imputed if missing (see 
Section 6.5.6) as 5. 
8.2.3. 
Solicited Events at Outcomes Assessment Visits #1 and #2 
Separately for Outcome Assessment Visit #1 and #2, using CC-V1 and CC-V2, respectively, a 
forest plot of 95% confidence intervals for the risk difference of each solicited event and the risk 
difference of any solicited, for each severity threshold (mild or greater, moderate or greater, or 
severe) will be produced (Figure 3, Figure 4, Figure 5 and Figure 6, Figure 7, Figure 8). Results 
will also be reported in tables (Table 18, Table 19, Table 20, Table 21, Table 22, and Table 23), 
and tests for differences in proportions between treatment arms will be given by Fisher’s exact 
tests. The Newcombe method with continuity correction will be used to compute all 95% 
confidence intervals for risk differences. 


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8.2.4. 
Resolution of Symptoms at Outcomes Assessment Visits #1 and #2 
Separately for Outcome Assessment Visit #1 and #2, using CC-V1 and CC-V2, respectively, a 
forest plot of 95% confidence intervals for the risk difference of lack of resolution of symptoms 
as well as the following: (1) fever (as defined in Section 6.5.2) (2) Elevated respiratory rate (RR 
>50 breaths/minute for children <24 months of age and >40 breaths/minute for children 24-71 
months of age) at the time of the Outcome Assessment Visit; and (3) Presence of cough Grade 2 
or 3 at the Outcome Assessment Visit will be given (Figure 9 and Figure 10). Results will also be 
reported in tables (Table 24 and Table 25), and tests for differences in proportions between 
treatment arms will be given by Fisher’s exact tests. The Newcombe method with continuity 
correction will be used to compute all 95% confidence intervals for risk differences. 
8.2.5. 
Adequate Clinical Response at Outcomes Assessment Visits #1 and #2 
Separately for Outcome Assessment Visit #1 and #2, using CC cohorts, a forest plot of 95% 
confidence intervals for the risk difference of adequate clinical response as well as the following 
interventions for persistent or worsening pneumonia: (1) ED/clinic visits, (2) hospitalizations, (3) 
surgical procedures, and (4) non-study systemic antibiotics will be given (Figure 11 and 
Figure 13). Results will also be reported in tables (Table 26 and Table 28), and tests for 
differences in proportions between treatment arms will be given by Fisher’s exact tests. The 
Newcombe method with continuity correction will be used to compute all 95% confidence 
intervals for risk differences. 
Separately for Outcome Assessment Visit #1 and #2, using CC cohorts, a forest plot of 95% 
confidence intervals for the risk difference of the following interventions for any reason: (1) 
ED/clinic visits, (2) hospitalizations, (3) surgical procedures, and (4) non-study systemic 
antibiotics will be given (Figure 12 and Figure 14). Results will also be reported in tables 
(Table 27 and Table 29), and tests for differences in proportions between treatment arms will be 
given by Fisher’s exact tests. The Newcombe method with continuity correction will be used to 
compute all 95% confidence intervals for risk differences. 
8.2.6. 
Ordinal Clinical Response at Outcomes Assessment Visits #1 and #2 
Analysis of the ordinal clinical response (OCR) at Outcome Assessment Visits #1 and #2.  
Separately for OCR at each of the two visits, a first ITT analysis (superiority/inferiority) will test 
the null hypothesis that 
Pr(OCR is better in short course) + 0.5 Pr(OCR is equal) = 0.5. 
A second ITT analysis (non-inferiority) will test the null hypothesis that  
Pr(OCR is better in short course) + 0.5 Pr(OCR is equal) < 0.4. 
ITT, CC, ATP, and worst case analyses will plot cumulative difference plots and test whether the 
overall distributions of OCR are equivalent between the treatment arms for OCR at each of the 
two visits. 
Cumulative difference plots (Figure 15, Figure 16, Figure 17, Figure 18 and Figure 19, 
Figure 20, Figure 21, Figure 22) are produced as follows.  For 𝑖𝑖∈{1,2,3,4,5,6,7}, the difference 
in proportions of subjects with OCR ≤𝑖𝑖 between treatment arms is plotted (𝑖𝑖 on x-axis and 


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difference in proportion on y-axis), together with 95% confidence intervals computed using the 
Newcombe method with continuity correction. 
For CC-V1, CC-V2, ATP-V1, and ATP-V2 analysis populations, OCRs will be summarized by 
treatment group and tests of overall distributions of OCR will be performed using the mean score 
statistic (QS). The mean score statistic is obtained from PROC FREQ in SAS using the “chisq” 
option and is denoted in output as the “Mantel-Haenszel Chi-Square” statistic. 
8.2.6.1. 
ITT Analyses of OCR at Outcomes Assessment Visit #1 
Twenty (20) multiple imputation datasets for OCR at Outcome Assessment Visit #1 will be 
generated in manner analogous to that described in Section 8.1.1, except using OCR at Outcome 
Assessment Visit #1 in place of DOOR at Outcome Assessment Visit #1 for the response. Also, 
analogous to Section 8.1.1, the Mann-Whitney U statistic will be computed for each of the 
datasets and combined using Rubin’s Rules to generate the test statistic W and a p-value for the 
test of the null hypothesis that 
Pr(OCR at Outcome Assessment Visit #1 is better in short course) + 0.5 Pr(OCR at Outcome 
Assessment Visit #1 is equal) = 0.5. 
The F-test using the W statistic will be inverted to produce a 95% confidence interval for 
Pr(OCR is better in short course) + 0.5 Pr(OCR is equal). Whether the lower bound of this 
confidence interval is greater than 0.4 will serve as a test of the non-inferiority null hypothesis 
that 
Pr(OCR at Outcome Assessment Visit #1 is better in short course) + 0.5 Pr(OCR at Outcome 
Assessment Visit #1 is equal) < 0.40. 
Results will be reported in Table 30. 
8.2.6.2. 
ITT Analyses of OCR at Outcomes Assessment Visit #2 
Twenty (20) multiple imputation datasets for OCR at Outcome Assessment Visit #2 will be 
generated in manner analogous to that described in 8.2.1, except using OCR at Outcome 
Assessment Visit #2 in place of DOOR at Outcome Assessment Visit #2 for the response. Also, 
analogous to 8.2.1, the Mann-Whitney U statistic will be computed for each of the datasets and 
combined using Rubin’s Rules to generate the test statistic W and a p-value for the test of the 
null hypothesis that 
Pr(OCR at Outcome Assessment Visit #2 is better in short course) + 0.5 Pr(OCR at Outcome 
Assessment Visit #2 is equal) = 0.5. 
The F-test using the W statistic will be inverted to produce a 95% confidence interval for 
Pr(OCR is better in short course) + 0.5 Pr(OCR is equal). Whether the lower bound of this 
confidence interval is greater than 0.4 will serve as a test of the non-inferiority null hypothesis 
that 
Pr(OCR at Outcome Assessment Visit #2 is better in short course) + 0.5 Pr(OCR at Outcome 
Assessment Visit #2 is equal) < 0.40. 
Results will be reported in Table 31. 


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8.2.6.3. 
Complete Case Analysis of the OCR at Outcome Assessment Visit #1 
Analysis will be performed as described in Section 8.2.6 using the CC-V1 population. Results 
will be reported in Table 32 and Table 33. 
8.2.6.4. 
Complete Case Analysis of the OCR at Outcome Assessment Visit #2 
Analysis will be performed as described in Section 8.2.6 using the CC-V2 population. Results 
will be reported in Table 34 and Table 35. 
8.2.6.5. 
According-to-Protocol Analysis of the OCR at Outcome Assessment Visit #1 
Analysis will be performed as described in Section 8.2.6 using the ATP-V1 population. Results 
will be reported in Table 36 and Table 37. 
8.2.6.6. 
According-to-Protocol Analysis of the OCR at Outcome Assessment Visit #2 
Analysis will be performed as described in Section 8.2.6 using the ATP-V2 population. Results 
will be reported in Table 38 and Table 39. 
8.2.6.7. 
Worst Case Analysis of the OCR at Outcome Assessment Visit #1 
Analysis will be performed as described in Section 8.2.6 using the ITT population with missing 
values imputed as follows. Subjects in the short course arm will have their ordinal clinical 
response imputed as 8. As an exception, subjects in the shorts course arm with OCR missing for 
Outcome Assessment Visit #1 but not for Outcome Assessment Visit #2 will have the OCR for 
Outcome Assessment Visit #1 imputed as the Outcome Assessment Visit #2 value or as 5, 
whichever value is larger. Subjects in the standard course arm will have their ordinal clinical 
response imputed as the value that would occur if all missing data was benign (no additional 
solicited events / cough / fever, etc.). Results will be reported in Table 40. 
8.2.6.8. 
Worst Case Analysis of the OCR at Outcome Assessment Visit #2 
Analysis will be performed as described in Section 8.2.6 using the ITT population with missing 
values imputed as follows. Subjects in the short course arm will have their ordinal clinical 
response imputed as 8. Subjects in the standard course arm will have their ordinal clinical 
response imputed as the value that would occur if all missing data was benign (no additional 
solicited events / cough / fever, etc.). Results will be reported in Table 41. 
8.2.7. 
Additional Analysis of Cough 
The proportion of subjects in each treatment group experiencing moderate or severe cough will 
be tabulated by day from Day 1 to Day 25 (as recorded from the memory aid), by visit, and 
overall, with 95% exact confidence intervals (Table 42). The proportion of subjects in each 
treatment group experiencing cough will also be tabulated by day from Day 1 to Day 25 (as 
recorded from the memory aid), by visit, and by severity level (Table 43 and Table 44). Finally, 
cough will be analyzed by taking the most severe response over the follow-up period, 
dichotomizing into a binary variable (none or mild versus moderate or severe) (Table 45). 
Proportions for these derived binary variables will be reported along with 95% exact confidence 
intervals. Comparisons of proportions by treatment groups will be given as odds ratios (with 


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95% exact confidence intervals) and p-values from Fisher’s Exact Tests. Cough severity will be 
listed by study day and study visit (Listing 15 and Listing 16). 
8.3. 
Exploratory Efficacy Analyses 
8.3.1. 
Complete Case Evaluation of DOOR at Outcome Assessment Visit #1, Minimum 
Required Difference in Days for Antibiotic Use “Tie-breaking” Varies 
k=1,2,3,4,5, or infinity 
In the primary RADAR/DOOR analysis, if two subjects from separate treatment arms have an 
equal ordinal clinical response but a difference in the duration of antibiotic use of at least k=1 
day, RADAR assigns a more favorable response to the subject with fewer days of antibiotic use. 
For a sensitivity analysis, the effect of increasing the minimum difference in the duration of 
antibiotic use (k=2,3,4, or 5, or infinity) before a favorable response is given to the subject with 
shorter duration of antibiotic use will be explored. The analysis of RADAR/DOOR with 
k=infinity is equivalent to comparison of OCR without regard for number of days of antibiotic 
use, and is included here for comparative purposes. For each value of k, bootstrapped confidence 
intervals of the probability of more favorable DOOR due to assignment to the 5-day antibiotic 
course will be computed and plotted versus k. Analysis will be performed separately for DOOR 
at Outcome Assessment Visit #1 and DOOR at Outcome Assessment Visit #2. Analyses will be 
performed using CC-V1/CC-V2 cohorts. Results will be reported in Table 46 and Figure 23. 
8.3.2. 
Stratified (ITT) Analyses of DOOR at Outcome Assessment Visit #1 
Analysis of DOOR at Outcome Assessment Visit #1 as described in Section 8.1.1 will be 
performed separately for each level of each stratification variable (e.g. an analysis of all subjects 
of age <24 months at enrollment, and a separate analysis of all subjects of age 24-71 months at 
enrollment) and by clinical site. Results will be reported Table 47. 
8.3.3. 
As Treated Analysis of Effect of Number of Days of Antibiotic Use on OCR at 
Outcome Assessment Visit #1 and Outcome Assessment Visit #2 
The analysis will be performed using the subset of the CC-V1 analysis population that did not 
receive off-study systemic antibiotic unrelated to pneumonia prior to Outcome Assessment Visit 
#1. The justification for excluding subjects with unrelated antibiotic use is that subjects receiving 
unrelated antibiotics are at risk for both improved outcomes due to ongoing antibiotic use as well 
as increased side effects related to antibiotics administration. The effect of the number of days of 
antibiotic use at Outcome Assessment Visit #1 on OCR at Outcome Assessment Visit #1 will be 
analyzed using a proportional odds model that simultaneously uses all cumulative logits (Agresti 
2003). 
Let K be the set of distinct OCR values observed at Outcome Assessment Visit #1, with the 
exception that the highest (worst) distinct value observed is not included in the set. 
Let Yi = the OCR of subject i at Outcome Assessment Visit #1. 
Let Xi = the number of days of antibiotic use at Outcome Assessment Visit #1 for subject i. 
αk, where k ϵ K, and β are parameters to be simultaneously estimated through maximum 
likelihood methods. 


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Then, proportional odds model with cumulative logits is defined as 
Logit [P(Yi > k)] = αk + β Xi ,             k ϵ K 
The following gives the interpretation of the model.  Suppose D is any non-negative integer. 
Then, log[odds(OCR>k | Xi = D+1) / odds(OCR>k | Xi = D)] = β. 
That is, for any k, where k is from the set of observed OCR values at Outcome Assessment Visit 
#1 besides the highest observed value, eβ gives the odds ratio of an OCR at Outcome Assessment 
Visit #1 greater than k for the effect of one additional day of use of antibiotic. 
It should be stated clearly that this analysis is “as treated” rather than “as randomized.” As such, 
causality cannot be inferred from a statistically significant association. This is especially true if 
subjects receiving off-study antibiotic not unrelated to the prior diagnosis of pneumonia are 
observed during the study. Such subjects will have a higher OCR and will also likely have more 
days of antibiotic use. 
This analysis will be repeated using the subset of the CC-V2 analysis population that did not 
receive off-study systemic antibiotic unrelated to pneumonia prior to Outcome Assessment Visit 
#2. The effect of the number of days of antibiotic use at Outcome Assessment Visit #2 on OCR 
at Outcome Assessment Visit #2 will be analyzed using logistic regression with a proportional 
odds assumption. Results from both analyses will be summarized in Table 48. The odds ratio for 
the proportional odds of an OCR at Outcome Assessment Visit #1 greater than k for the effect of 
one additional day of use of antibiotic will be reported with a 95% Wald confidence interval and 
p-value from a Wald test. For p<0.05, an association between OCR and the number of days of 
antibiotic use, as treated, will be concluded. 
8.4. 
Imputation of Missing Data 
8.4.1. 
Multiple Imputation of Missing Ordinal Clinical Response and DOOR at 
Outcome Assessment Visit #1 and Outcome Assessment Visit #2 
Several analyses, including the primary analysis, depend on multiple imputation of DOOR or 
OCR at Outcome Assessment Visit #1 or Outcome Assessment Visit #2. Multiple imputations of 
each of these missing endpoints will be performed independently, and each subject will have 
their missing endpoints imputed independently of other subject’s imputations using a subject-
specific imputation model. 
As a first step to multiple imputation, an ordered list of variables to include in the subject-
specific imputation model is constructed. Ordering is specified so that exact imputation results 
from final data are prespecified may be replicated in SAS (using seeds described below). The 
complete ordered list of variables for the imputation models for DOOR at Outcome Assessment 
Visit #1 and OCR at Outcome Assessment Visit #1 is below. 
• 
Indicator of subject enrolled at the site with the second most number of subjects enrolled 
(binary indicator) 
• 
Indicator of subject enrolled at the site with the third most number of subjects enrolled 
(binary indicator) 


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• 
Indicator of subject enrolled at the site with the least number of subjects enrolled (binary 
indicator) 
o Note: the site with the most number of subjects enrolled is reference for site. 
Language is written to allow for an arbitrary number of sites. In the event of a number 
of ties for the number of subjects enrolled, tied sites will be ordered in ascending 
alphanumeric order in the list of model variables. 
• 
Indicator of amoxicillin (not amoxicillin placebo) as study treatment (binary indicator) 
• 
Indicator of amoxicillin-clavulanate (not amoxicillin-clavulanate placebo) as study 
treatment (binary indicator) 
• 
Indicator of cefdinir (not cefdinir placebo) as study treatment (binary indicator) 
o Note: placebo is the reference group for study treatment 
• 
Indicator for amoxicillin-clavulanate as initial antibiotic (binary indicator) 
• 
Indicator for cefdinir as initial antibiotic (binary indicator)  
o Note: amoxicillin is the reference group for initial antibiotic 
• 
Indicator for age ≥ 2 years at enrollment (binary indicator) 
• 
Indicator for initial treatment site for pneumonia at an emergency department (binary 
indicator) 
• 
OCR at Outcome Assessment Visit #2 (imputed OCRs will not be used) 
• 
Severity of cough on Day 1 as recorded on Solicited Events form (0, 1, 2, or 3) 
o Note: amoxicillin is the reference group for initial antibiotic 
• 
Severity of most severe solicited event (besides cough) on Day 1(0, 1, 2, or 3) 
o Note: Some missing values for Day 1 will first be imputed as described in 
Section 6.5.4 
• 
Severity of cough on Day 2 as recorded on Solicited Events form (0, 1, 2, or 3) 
• 
Severity of most severe solicited event (besides cough) on Day 2 (0, 1, 2, or 3)  
o Note: Some missing values for Day 2 will first be imputed as described in 
Section 6.5.4 
• 
Severity of cough on Day 3 as recorded on Solicited Events form (0, 1, 2, or 3) 
• 
Severity of most severe solicited event (besides cough) on Day 3 (0, 1, 2, or 3) 
o Note: Some missing values for Day 3 will be first imputed as described in 
Section 6.5.4 
• 
Severity of cough on Day 4 as recorded on Solicited Events form (0, 1, 2, or 3) 
• 
Severity of most severe solicited event (besides cough) on Day 4 (0, 1, 2, or 3) 
o Note: Some missing values for Day 4 will first be imputed as described in 
Section 6.5.4 


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• 
Severity of cough on Day 5 as recorded on Solicited Events form (0, 1, 2, or 3) 
• 
Severity of most severe solicited event (besides cough) on Day 5 (0, 1, 2, or 3) 
o Note: Some missing values for Day 5 will first be imputed as described in 
Section 6.5.4 
For DOOR and OCR at Outcome Assessment Visit #2, the complete list of model variables is 
identical to the above, but with OCR at Outcome Assessment Visit #2 replaced with OCR at 
Outcome Assessment Visit #1. Additionally, cough severity and most severe solicited event are 
listed up to Day 18 rather than Day 5. 
The actual list of model variables for each subject-specific imputation model will follow the 
ordering above but omit variables with missing values. The below pseudo-code / SAS code 
outlines the creation of 20 multiple imputation datasets. Note that the seeds used in the actual 
analysis must follow the specification given in the pseudo-code and subjects must be processed 
in the order described in the pseudo-code. OCR will simultaneously be imputed with DOOR at 
each respective Outcome Assessment Visit. The pseudo-code is in terms of the Outcome 
Assessment Visit #1 endpoints, but the general logic is also applicable to the Outcome 
Assessment Visit #2 endpoints (with references to “V1” replaces with references to “V2”). 
DEFINE i=index variable for subjects having DOOR imputed. 
 
Subjects requiring imputation are sorted in ascending order 
 
by PATID. 
DEFINE N=number of subjects requiring imputation 
DEFINE g&i=analysis dataset containing predictors and DOOR for  
CC-V1 subjects as well as subject i (only one subject not in  
CC-V1 included).  Note that CC-V1 subjects that are missing a 
value 
for one or more variables in the subject-specific imputation 
model are excluded. 
DEFINE imp_g&i = g&i, with 20 imputed values for the missing DOOR 
 
added by PROC MI 
DEFINE &&modelVars_&i = list of observed variables in subject i, to 
 
be used for imputation of DOOR and OCR. 
 
%do i=1 %to &N; 
PROC MI data=g&i out=imp_g&i seed=1200&i NIMPUTE=20 noprint; 
 
var &&modelVars_&i DOOR OCR; 
 
monotone reg(DOOR_V1 = &&modelVars_&i);  
 
monotone reg(OCR_V1 = &&modelVars_&i); 


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run; 
%end; 
 
imp_g&i will be subset to contain only rows for the subjects with 
imputed DOOR and merged together and with CC-V1 data to create the 
twenty complete multiply imputed datasets 
******************************************************************** 


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9. 
SAFETY EVALUATION 
Subjects in safety analyses will be analyzed according to randomization assignment, using the 
safety analysis population. 
9.1. 
Demographic and Other Baseline Characteristics 
Summaries of age, gender, enrollment site, ethnicity, race, initial antibiotic therapy, initial 
treatment locations, and age group (<24 months vs. 24-71 months) will be presented by site 
(Table 9 and Table 10) or by treatment group and overall (Table 11 and Table 12). Ethnicity will 
be categorized as Hispanic or Latino, or not Hispanic and not Latino. In accordance with NIH 
reporting policy, a subject’s guardians may designate the subject as belonging to more than one 
race or may refuse to identify a race, the latter reflected in the CRF as “No” to each racial option. 
Summaries of subject’s medical history will be presented by MedDRA® system organ class 
(SOC) and treatment group (Table 13). 
Individual subject listings for all demographics (Listing 5) and pre-existing medical conditions 
(Listing 6) will be presented. 
9.1.1. 
Concurrent Illnesses and Medical Conditions 
Physical assessment findings from the enrollment visit, and any follow up visits, will be included 
in Listing 11. 
9.1.2. 
Prior and Concurrent Medications 
All concomitant medications taken within 30 days of signing the informed consent or during the 
study period will be recorded. Concomitant medications will be coded to the Anatomical 
Therapeutic Classification using the WHO Drug Dictionary. A by-subject listing of concomitant 
medication use will be presented (Listing 12). The use of concomitant medications during the 
study will be summarized by ATC1, ATC2 code and treatment group (Table 56). 
9.2. 
Measurements of Treatment Compliance 
Treatment was administered to subjects at their homes by a parent or caregiver. The number of 
subjects receiving the first dose of study product will be tabulated by site, treatment group, and 
time period (Table 6). The number of doses of study product administered will be presented by 
treatment group (Table 7, Listing 7). 
9.3. 
Adverse Events 
When calculating the incidence of AEs over multiple days (i.e., on a per subject basis), each 
subject will only be counted once and any repetitions of AEs within a subject will be ignored; the 
denominator will be the total population size on the first day of the time period (Day 1). For 
tabulation of AEs by day, the denominator will be the number of subjects enrolled and not 
withdrawn from the study by the day being described. All AEs reported will be included in the 
summaries and analyses. 


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9.3.1. 
Solicited Events  
Solicited events will be captured daily until Outcome Assessment Visit #1; thereafter, 
parents/legal guardians will report symptoms based on memory aid and medical interview by 
study staff. For those with multiple solicited events, the ordinal response table will be based 
upon the most severe solicited event. 
Solicited events were recorded for trial Days 1-25, or until study completion or termination, as 
the maximum severity for each day. Target solicited events include irritability, vomiting, 
diarrhea, allergic reaction, stomatitis, and candidiasis. 
The proportion of subjects in each treatment group experiencing each solicited event with mild 
or greater severity will be tabulated by day and overall (Table 49 and Table 50). The proportion 
of subjects in each treatment group experiencing each solicited event will also be tabulated by 
day and severity level (Table 51 and Table 52). Finally, solicited events will be analyzed by 
taking the most severe response over the follow-up period, dichotomizing into a binary variable 
(none or mild versus moderate or severe) (Table 53). Proportions for these derived binary 
variables will be reported along with 95% exact confidence intervals. Comparisons of 
proportions by treatment groups will be given as odds ratios (with 95% exact confidence 
intervals) and p-values from Fisher’s Exact Tests. 
The maximum severity occurrence of each solicited event and cough (proportion of subjects for 
each severity level) will be plotted for each solicited adverse event (Figure 24). Solicited events 
by subject will also be presented (Listing 8). 
9.3.2. 
Unsolicited Adverse Events 
As the safety profile of amoxicillin, amoxicillin-clavulanate, and cefdinir are well established, 
and this trial is not powered to detect new, unknown safety signals, there will be no unsolicited 
event collection during this study and only protocol-defined SAE’s will be collected. 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse 
Events 
Detailed narratives will be given for any deaths or other protocol-defined SAEs that occurred 
during the study. Listings of SAEs will be presented including subject ID, AE description, AE 
onset date/end date, reason reported as an SAE, relationship to treatment, alternate etiology if not 
related, outcome, and duration of event (days) (Listing 9). SAEs will also be listed in Table 54. 
9.5. 
Vital Signs and Physical Evaluations 
Vital signs will be taken at the enrollment visit, Outcome Assessment Visit #1, and Outcome 
Assessment Visit #2. For each visit, by treatment group, the mean, median, standard deviation, 
min, and max of vital sign will be calculated for temperature, respiration rate, and pulse 
(Table 55). Individual vital signs measurements will be listed (Listing 10). 
9.6. 
Concomitant Medications 
Concomitant medications will be coded to the Anatomical Therapeutic Classification using the 
WHO Drug Dictionary. The use of prior and concomitant medications taken during the study 


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will be recorded on the CRFs. A by-subject listing of concomitant medication use will be 
presented. The use of concomitant medications during the study will be summarized by ATC1, 
ATC2 code and treatment group for the Safety population (Table 56). 
9.7. 
Other Safety Measures 
The number and percent of subjects visiting an emergency department, primary care provider, 
study physician, urgent care, or having some other type of medically attended visit due to 
worsening study pneumonia will be presented together with whether the subject received 
antibiotic, surgical treatment, or was hospitalized due to pneumonia or a complication of 
pneumonia (Table 57). Medically attended visits will also be listed (Listing 13 and Listing 14). 
Presence of fever will be listed by visit (Listing 17 and Listing 18). 


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10. 
OTHER ANALYSES 
No other analyses are planned. 


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11. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.001 will be 
reported as “<0.001”; p-values greater than 0.999 will be reported as “> 0.999“. The mean, 
standard deviation, and any other statistics other than quantiles, will be reported to one decimal 
place greater than the original data. Quantiles, such as median, or minimum and maximum will 
use the same number of decimal places as the original data. Proportions will be presented as two 
decimal places; values <0.01 will be presented as “<0.01”. Percentages will be reported to the 
nearest whole number; values < 1% will be presented as “<1”. Estimated parameters, not on the 
same scale as raw observations (e.g., regression coefficients) will be reported to 3 significant 
figures. 


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12. 
TECHNICAL DETAILS 
SAS version 9.3 or above or R version 3.2 or above will be used to perform analyses and to 
generate all tables, figures and listings. 


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13. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY 
OR PLANNED ANALYSES 
Changes in the Conduct of the Study 
Enrollment into the study was initiated under protocol version 2.0. Substantive changes to the 
protocol after study initiation are provided below. 
Substantive changes in protocol version 3.0 
• Removed 200mg/5mL amoxicillin and 200mg/5mL amoxicillin-clavulanate as possible 
dose strengths under Protocol Section 6.1.2. No subjects were prescribed under this dose. 
• Clarified timing of interim analysis to be after at least 30% of the targeted subjects have 
completed the study instead of approximately 30%. 
Changes to the Planned Analyses 
There are no changes to the planned analyses as described in the protocol. 


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14. 
REFERENCES 
Agresti, Alan. Categorical Data Analysis 2nd Ed. John Wiley & Sons, 2003 
Evans, Scott R., et al. "Desirability of outcome ranking (DOOR) and response adjusted for 
duration of antibiotic risk (RADAR)." Clinical Infectious Diseases (2015): civ495. 
Evans, Scott R., Lingling Li, and L. J. Wei. "Data monitoring in clinical trials using prediction." 
Drug Information Journal 41.6 (2007): 733-742. 
Greenberg, David, et al. "Short-course antibiotic treatment for community-acquired alveolar 
pneumonia in ambulatory children: A double-blind, randomized, placebo-controlled trial." The 
Pediatric infectious disease journal 33.2 (2014): 136-142. 
Lehmann, Erich Leo, and H. J. D'abrera. Nonparametrics: statistical methods based on ranks. 
Holden-Day, 1975. 
Li, Lingling, et al. "Predicted interval plots (PIPS): a graphical tool for data monitoring of 
clinical trials." Statistics in biopharmaceutical research 1.4 (2009): 348-355. 
Marshall, A., Altman, D.G., Holder, R.L. and Royston, P., 2009. Combining estimates of interest 
in prognostic modelling studies after multiple imputation: current practice and guidelines. BMC 
medical research methodology, 9(1), p.1. 
Mann, Henry B., and Donald R. Whitney. "On a test of whether one of two random variables is 
stochastically larger than the other." The annals of mathematical statistics (1947): 50-60. 
Noether, Gottfried E. "Sample size determination for some common nonparametric tests." 
Journal of the American Statistical Association 82.398 (1987): 645-647. 
Zhao, Yan D., Dewi Rahardja, and Yongming Qu. "Sample size calculation for the Wilcoxon–
Mann–Whitney test adjusting for ties." Statistics in medicine 27.3 (2008): 462-468. 


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15. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 
 


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APPENDICES 


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APPENDIX 1. TABLE MOCK-UPS 
LIST OF TABLES 
Table 1: 
Ordinal Outcome ..........................................................................................................5 
Table 2: 
Distribution of Protocol Deviations by Category, Type and Treatment Group .........57 
Table 3: 
Solicited Adverse Event Grading Scale ......................................................................58 
Table 4: 
Subject Disposition by Treatment Group ...................................................................59 
Table 5: 
Analysis Populations by Treatment Group .................................................................60 
Table 6: 
Dates of First Treatment by Site and Treatment Group .............................................62 
Table 7: 
Treatment Compliance by Treatment Group ..............................................................63 
Table 8: 
Ineligibility Summary of Screen Failures ...................................................................64 
Table 9: 
Summary of Categorical Demographic and Baseline Characteristics by Site ............65 
Table 10: Summary of Continuous Demographic and Baseline Characteristics by Site ............66 
Table 11: Summary of Categorical Demographic and Baseline Characteristics by 
Treatment Group - All Enrolled Subjects ...................................................................67 
Table 12: Summary of Continuous Demographic and Baseline Characteristics by 
Treatment Group - All Enrolled Subjects ...................................................................68 
Table 13: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group ................................................................69 
Table 14: Primary ITT Analysis of DOOR at Outcome Assessment Visit #1 ...........................70 
Table 15: Primary ITT Analysis of DOOR at Outcome Assessment Visit #2 ...........................71 
Table 16: Sensitivity Analyses of DOOR at Outcome Assessment Visit #1 ..............................72 
Table 17: Sensitivity Analyses of DOOR at Outcome Assessment Visit #2 ..............................73 
Table 18: Risk of Mild, Moderate, or Severe Solicited Event from Day 1 to Day 5 
(CC-V1 Cohort) by Treatment Group ........................................................................74 
Table 19: Risk of Moderate or Severe Solicited Event from Day 1 to Day 5 (CC-V1 
Cohort) by Treatment Group ......................................................................................75 
Table 20: Risk of Severe Solicited Event from Day 1 to Day 5 (CC-V1 Cohort) by 
Treatment Group .........................................................................................................76 
Table 21: Risk of Mild, Moderate, or Severe Solicited Event from Day 1 to Day 18 
(CC-V2 Cohort) by Treatment Group ........................................................................77 
Table 22: Risk of Moderate or Severe Solicited Event from Day 1 to Day 18 (CC-V2 
Cohort) by Treatment Group ......................................................................................78 
Table 23: Risk of Severe Solicited Event from Day 1 to Day 18 (CC-V2 Cohort) by 
Treatment Group .........................................................................................................79 


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Table 24: Lack of Resolution of Symptoms and Its Components at Outcome 
Assessment Visit #1 (CC-V1 Cohort) by Treatment Group .......................................80 
Table 25: Lack of Resolution of Symptoms and Its Components at Outcome 
Assessment Visit #2 (CC-V2 Cohort) by Treatment Group .......................................81 
Table 26: Risk of Lack of Adequate Clinical Response and Its Components from Day 
1 to Day 5 (CC-V1 Cohort) by Treatment Group .......................................................82 
Table 27: Any Receipt of Non-Study Antibiotics and Medically Attended Visits from 
Day 1 to Day 5 (CC-V1 Cohort) by Treatment Group ...............................................83 
Table 28: Risk of Lack of Adequate Clinical Response and Its Components from Day 
1 to Day 18 (CC-V2 Cohort) by Treatment Group .....................................................84 
Table 29: Any Receipt of Non-Study Antibiotics or Medically Attended Visit from 
Day 1 to Day 18 (CC-V2 Cohort) by Treatment Group .............................................85 
Table 30: ITT Analysis of Ordinal Clinical Response at Outcome Assessment Visit #1 ..........86 
Table 31: ITT Analysis of Ordinal Clinical Response at Outcome Assessment Visit #2 ..........87 
Table 32: Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #1 (CC-V1) ....................................................................................88 
Table 33: Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #1 (CC-V1) - Comparison of Distributions ...................................89 
Table 34: Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #2 (CC-V2) ....................................................................................90 
Table 35: Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #2 (CC-V2) - Comparison of Distributions ...................................91 
Table 36: According-to-Protocol Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #1 (ATP-V1) ..................................................................................92 
Table 37: Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #1 (ATP-V1) - Comparison of Distributions .................................93 
Table 38: According-to-Protocol Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #2 (ATP-V2) ..................................................................................94 
Table 39: Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #2 (ATP-V2) - Comparison of Distributions .................................95 
Table 40: Worst Case Analysis of Ordinal Clinical Response at Outcome Assessment 
Visit #1 (ITT Cohort) ..................................................................................................96 
Table 41: Worst Case Analysis of Ordinal Clinical Response at Outcome Assessment 
Visit #2 (ITT Cohort) ..................................................................................................97 
Table 42: Number and Percentage of Subjects Experiencing Moderate or Severe 
Cough by Day and Treatment Group..........................................................................98 
Table 43: Number and Percentage of Subjects Experiencing Coughing by Maximum 
Severity and Treatment Group – Standard Course .....................................................99 


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Table 44: Number and Percentage of Subjects Experiencing Coughing by Maximum 
Severity and Treatment Group – Short Course.........................................................100 
Table 45: Number and Percentage of Subjects Experiencing Cough of Mild Severity or 
Greater, Moderate Severity or Greater, or Severe Severity Over the Follow-
up Period by Treatment Group .................................................................................101 
Table 46: CC-V1 Evaluation of DOOR at Outcome Assessment Visit #1, Minimum 
Required Difference in Days for Antibiotic Use “Tie-Breaking” Varies 
k=1,2,3,4,5, or Infinity ..............................................................................................102 
Table 47: ITT Evaluation of DOOR at Outcome Assessment Visit #1, Analysis By 
Stratification Variable and Clinical Site ...................................................................103 
Table 48: As Treated Analysis of Association between Ordinal Clinical Response and 
the Number of Days of Antibiotic Use at Outcome Assessment Visit #1 and 
Outcome Assessment Visit #2 ..................................................................................104 
Table 49: Number and Percentage of Subjects Experiencing Solicited Events with 95% 
Confidence Intervals by Symptom, Dose, and Treatment Group - Standard 
Course .......................................................................................................................105 
Table 50: Number and Percentage of Subjects Experiencing Solicited Events with 95% 
Confidence Intervals by Symptom, Dose, and Treatment Group – Short 
Course .......................................................................................................................105 
Table 51: Number and Percentage of Subjects Experiencing Solicited Events by 
Symptom, Maximum Severity, Dose, and Treatment Group – Standard 
Course .......................................................................................................................106 
Table 52: Number and Percentage of Subjects Experiencing Solicited Events by 
Symptom, Maximum Severity, Dose, and Treatment Group – Short Course ..........108 
Table 53: Number and Percentage of Subjects Experiencing Solicited Adverse Events 
of Mild Severity or Greater, Moderate Severity or Greater, or Severe 
Severity Over the Follow-up Period by Treatment Group .......................................110 
Table 54: Listing of Serious Adverse Events ...........................................................................111 
Table 55: Summary of Vital Signs by Visit and Treatment Group ..........................................115 
Table 56: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Treatment Group ................................................116 
Table 57: Medically Attended Visits ........................................................................................117 
 


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10.2 
Protocol Deviations 
Table 2: 
Distribution of Protocol Deviations by Category, Type and Treatment Group 
Category 
Deviation Type 
Standard Course  
(N=X) 
Short Course 
(N=X) 
All Subjects 
(N=X) 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
Eligibility/enrollment 
Any type 
 
 
 
 
 
 
 
Did not meet inclusion criterion 
x 
x 
x 
x 
x 
x 
 
Met exclusion criterion 
 
 
 
 
 
 
 
ICF not signed prior to study 
procedures 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Treatment administration 
schedule 
Any type 
 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
 
Missed visit/visit not conducted 
 
 
 
 
 
 
 
Missed treatment administration 
 
 
 
 
 
 
 
Delayed treatment administration 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Follow-up visit schedule 
Any type 
 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
 
Missed visit/visit not conducted 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Protocol 
procedure/assessment 
Any type 
 
 
 
 
 
 
 
Incorrect version of ICF signed 
 
 
 
 
 
 
 
Other specimen not collected 
 
 
 
 
 
 
 
Specimen result not obtained 
 
 
 
 
 
 
 
Required procedure not conducted 
 
 
 
 
 
 
 
Required procedure done incorrectly 
 
 
 
 
 
 
 
Study product temperature excursion 
 
 
 
 
 
 
 
Specimen temperature excursion 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Treatment administration 
Any type 
 
 
 
 
 
 
 
Required procedure done incorrectly 
 
 
 
 
 
 
 
Study product temperature excursion 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 


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12.2.2 Displays of Adverse Events 
Table 3: 
Solicited Adverse Event Grading Scale 
Symptom 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Irritability 
More irritable or fussy than 
usual but can be consoled; 
no interference with 
smiling/playing 
Irritability or fussiness that is 
difficult to console and 
interferes with smiling and 
playing 
Irritability or fussiness that lasts 
for more than 4 consecutive 
hours in a 24 hour period or 
cannot be consoled 
Vomiting  
1 episode/day  
2-3 episodes/day  
≥4 episodes/day  
Diarrhea  
Looser than normal stools 
occurring 3-6 times/day 
Looser than normal stools 
occurring >6 times/day  
Bloody diarrhea, or diarrhea 
that requires medical 
intervention, laboratory testing, 
or hospitalization 
Allergic 
Reaction 
Localized rash or pruritus 
without rash 
Diffuse rash (maculopapular 
or urticarial)  
Generalized rash consistent 
with Stevens-Johnson 
Syndrome, erythema 
multiforme, or toxic epidermal 
necrolysis; anaphylaxis; or 
angioedema 
Stomatitis 
Oral lesions associated 
with parenteral report of 
mild oral discomfort  
Oral lesions associated with 
difficulty swallowing, but able 
to eat and drink 
Oral lesions associated with 
inability to swallow solids or 
liquids; requires medical 
intervention, IV fluids, or 
hospitalization 
Candidiasis 
Mild mucocutaneous 
candidiasis or diaper 
dermatitis, with no 
treatment or topical 
treatment only 
Moderate mucocutaneous 
candidiasis requiring oral 
antimicrobial treatment 
Severe mucocutaneous 
candidiasis; requires medical 
intervention, intravenous 
treatment, or hospitalization 
 


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14.1 
Description of Study Subjects 
14.1.1 Disposition of Subjects 
Table 4: 
Subject Disposition by Treatment Group 
Subject 
Disposition  
Standard Course 
(N=X) 
Short Course 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Screened 
-- 
-- 
-- 
-- 
x 
-- 
Enrolled/Randomized 
x 
100 
x 
100 
x 
100 
Received First Dose of Treatment 
x 
xx 
x 
xx 
x 
xx 
Received All Scheduled 
Treatmenta 
x 
xx 
x 
xx 
x 
xx 
Completed All Future Use Sample 
Collection 
 
 
 
 
 
 
Completed Outcome Assessment 
Visit #1 (Study Day 6-10)a 
 
 
 
 
 
 
Completed Outcome Assessment 
Visit #2 (Study Day 19-25) a 
 
 
 
 
 
 
a Refer to Listing 1 for reasons subjects discontinued or terminated early. 
b Refer to Listing 4 for reasons subjects are excluded from the Analysis populations. 
 


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Table 5: 
Analysis Populations by Treatment Group 
Analysis Populations 
Reason Subjects Excluded 
Standard Course  
(N=X) 
Short Course 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
% 
n 
ITT1 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
 
Became ineligible before taking 
study product 
 
 
 
 
 
 
CC-V12 
Any Reason 
 
 
 
 
 
 
 
Subject not treated with study 
product 
 
 
 
 
 
 
 
Early termination before Outcome 
Assessment Visit #1 
 
 
 
 
 
 
 
-Reason 1 for termination 
 
 
 
 
 
 
 
-Reason 2 for termination 
 
 
 
 
 
 
 
Completed Outcome Assessment 
Visit #1, but Missing DOOR 
Component 
 
 
 
 
 
 
 
-Adequate Clinical Response 
 
 
 
 
 
 
 
-Resolution of Symptoms 
 
 
 
 
 
 
 
-Solicited Event Severity Days 1-5 
 
 
 
 
 
 
 
-Number of Days of Antibiotic Use 
 
 
 
 
 
 
CC-V2 
Any Reason 
 
 
 
 
 
 
 
Subject not treated with study 
product 
 
 
 
 
 
 
 
Early termination before Outcome 
Assessment Visit #2 
 
 
 
 
 
 
 
-Reason 1 for termination 
 
 
 
 
 
 
 
-Reason 2 for termination 
 
 
 
 
 
 
 
Completed Outcome Assessment 
Visit #2, but Missing DOOR 
Component 
 
 
 
 
 
 
 
-Adequate Clinical Response 
 
 
 
 
 
 
 
-Resolution of Symptoms 
 
 
 
 
 
 
 
-Solicited Event Severity Days 1-8 
 
 
 
 
 
 
 
-Number of Days of Antibiotic Use 
 
 
 
 
 
 
ATP-V13 
Any Reason 
 
 
 
 
 
 
 
The subject was excluded from 
CC-V1 cohort. 
 
 
 
 
 
 


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Analysis Populations 
Reason Subjects Excluded 
Standard Course  
(N=X) 
Short Course 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
% 
n 
 
Subject did not receive at least one 
dose of study product each day 
from Day 1 to Day 5 
 
 
 
 
 
 
 
Major protocol deviation 
 
 
 
 
 
 
 
-Outcome Assessment Visit #1 
occurred out of the protocol 
defined window of Day 6-10 
 
 
 
 
 
 
 
-Outcome Assessment Visit #1 did 
not occur as an in-person visit 
 
 
 
 
 
 
ATP-V2 
Any Reason 
 
 
 
 
 
 
 
The subject was excluded from 
CC-V2 cohort. 
 
 
 
 
 
 
 
Subject did not receive at least one 
dose of study product each day 
from Day 1 to Day 5 
 
 
 
 
 
 
 
Major protocol deviation 
 
 
 
 
 
 
 
-Outcome Assessment Visit #2 
occurred out of the protocol 
defined window of Day 19-25 
 
 
 
 
 
 
 
-Outcome Assessment Visit #2 did 
not occur as an in-person visit 
 
 
 
 
 
 
1 ITT = Intent-to-Treat 
2 CC = Complete Case 
3 ATP = According-to-Protocol 
 


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Table 6: 
Dates of First Treatment by Site and Treatment Group 
Site 
Treatment Group 
July 2016 - June 2017 
July 2017 - June 2018 
July 2018 - June 2019 
July 2019 - November 2019 
Children’s Hospital of Philadelphia 
Standard Course 
x 
x 
x 
x 
Short Course 
x 
x 
x 
x 
Children’s Hospital of Pittsburgh 
Standard Course 
x 
x 
x 
x 
Short Course 
x 
x 
x 
x 
Cincinnati Children’s Hospital 
Standard Course 
x 
x 
x 
x 
Short Course 
x 
x 
x 
x 
Duke University 
Standard Course 
x 
x 
x 
x 
Short Course 
x 
x 
x 
x 
Vanderbilt University 
Standard Course 
x 
x 
x 
x 
Short Course 
x 
x 
x 
x 
Any Site 
Standard Course 
x 
x 
x 
x 
Short Course 
x 
x 
x 
x 
Any 
Any 
x 
x 
x 
x 
[Programming Note: Rows will be added for additional sites that enroll at least one subject, as needed.] 
 


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Table 7: 
Treatment Compliance by Treatment Group 
 
Number of Doses Administered   n (%) 
Treatment 
Group 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Standard 
Course 
(N=X) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Short Course 
(N=X) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 


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Table 8: 
Ineligibility Summary of Screen Failures 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
Number of Times Item Marked Ineligible1 
Inclusion and Exclusion 
Number of subjects failing any eligibility criterion 
x 
Inclusion 
Any inclusion criterion 
x 
 
[inclusion criterion 1] 
x 
 
[inclusion criterion 2] 
x 
 
[inclusion criterion 3] 
x 
Exclusion 
Any exclusion criterion 
x 
 
[exclusion criterion 1] 
x 
 
[exclusion criterion 2] 
x 
 
[exclusion criterion 3] 
x 
1 More than one criterion may be marked per subject. 
 


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14.1.2 Demographic Data by Study Group 
Table 9: 
Summary of Categorical Demographic and Baseline Characteristics by Site 
Demographic 
Category 
Characteristic 
Children’s 
Hospital of 
Philadelphia 
(N=X) 
Children’s 
Hospital of 
Pittsburgh 
(N=X) 
Cincinnati 
Children’s 
Hospital 
(N=X) 
Duke 
University 
(N=X) 
Vanderbilt 
University 
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Female 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Ethnicity  
Not Hispanic or Latino 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Hispanic or Latino 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Not Reported 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Race  
American Indian or Alaska Native 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Asian 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Native Hawaiian or Other Pacific Islander 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Black or African American 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
White 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Multi-Racial 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Initial Antibiotic 
Amoxicillin 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Amoxicillin-Clavulanate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Cefdinir 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Initial Site of Treatment 
ED 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Out-Patient/Urgent Care 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Age Group 
<24 Months 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
24-71 Months 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[Programming Note: Columns will be added for additional sites that enroll at least one subject, as needed.] 


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Table 10: 
Summary of Continuous Demographic and Baseline Characteristics by Site 
Variable 
Statistic 
Children’s 
Hospital of 
Philadelphia 
(N=X) 
Children’s 
Hospital of 
Pittsburgh 
(N=X) 
Cincinnati 
Children’s 
Hospital 
(N=X) 
Duke 
University 
(N=X) 
Vanderbilt 
University 
(N=X) 
All 
Subjects 
(N=X) 
Age (Months) 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard 
Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
x 
[Programming Note: Columns will be added for additional sites that enroll at least one subject, as 
needed.] 
 


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Table 11: 
Summary of Categorical Demographic and Baseline Characteristics by 
Treatment Group - All Enrolled Subjects 
Demographic Category 
Characteristic 
Standard 
Course 
(N=X) 
Short Course 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Sex 
Male 
x 
x 
x 
x 
x 
x 
 
Female 
x 
x 
x 
x 
x 
x 
Ethnicity 
Not Hispanic or Latino 
x 
x 
x 
x 
x 
x 
 
Hispanic or Latino 
x 
x 
x 
x 
x 
x 
 
Not Reported 
x 
x 
x 
x 
x 
x 
 
Unknown 
x 
x 
x 
x 
x 
x 
Race 
American Indian or Alaska Native 
x 
x 
x 
x 
x 
x 
 
Asian 
x 
x 
x 
x 
x 
x 
 
Native Hawaiian or Other Pacific 
Islander 
x 
x 
x 
x 
x 
x 
 
Black or African American 
x 
x 
x 
x 
x 
x 
 
White 
x 
x 
x 
x 
x 
x 
 
Multi-Racial 
x 
x 
x 
x 
x 
x 
 
Unknown 
x 
x 
x 
x 
x 
x 
Initial Antibiotic 
Amoxicillin 
x 
x 
x 
x 
x 
x 
 
Amoxicillin-Clavulanate 
x 
x 
x 
x 
x 
x 
 
Cefdinir 
x 
x 
x 
x 
x 
x 
Initial Site of Treatment 
ED 
x 
x 
x 
x 
x 
x 
 
Out-Patient/Urgent Care 
x 
x 
x 
x 
x 
x 
Age Group 
<24 Months 
x 
x 
x 
x 
x 
x 
 
24-71 Months 
x 
x 
x 
x 
x 
x 
Clinical Trial Site 
Children’s Hospital of Philadelphia 
x 
x 
x 
x 
x 
x 
 
Children’s Hospital of Pittsburgh 
x 
x 
x 
x 
x 
x 
 
Cincinnati Children’s Hospital 
x 
x 
x 
x 
x 
x 
 
Duke University 
x 
x 
x 
x 
x 
x 
 
Vanderbilt University 
x 
x 
x 
x 
x 
x 
 


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Table 12: 
Summary of Continuous Demographic and Baseline Characteristics by 
Treatment Group - All Enrolled Subjects 
Variable 
Statistic 
Standard Course 
(N=X) 
Short Course 
(N=X) 
All Subjects 
(N=X) 
Age (Months) 
Mean 
xx 
xx 
xx 
 
Standard Deviation 
xx 
xx 
xx 
 
Median 
x 
x 
x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
 


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14.1.3 Prior and Concurrent Medical Conditions 
Table 13: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class and Treatment 
Group 
MedDRA System Organ Class 
Standard Course 
(N=X) 
Short Course 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any SOC 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
 
 
 
 
 
 
[SOC 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N=Number of subjects enrolled; n = Number of subjects reporting medical history within the specified SOC. A subject is only counted once per SOC. 
 


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14.2 
Efficacy/Immunogenicity Data 
Table 14: 
Primary ITT Analysis of DOOR at Outcome Assessment Visit #1 
Statistic 
Value 
Subjects with all DOOR components measured – n (%) 
x (x) 
Subjects with one or more DOOR components imputed – n (%) 
x (x) 
Pr(Higher DOOR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
P-value2 
x.xxx 
1 Probability of Higher DOOR in Short-Course Arm at Outcome Assessment Visit #1 + 0.5 Probability of Equal 
DOOR. Confidence interval obtained through inversion of the F-test used to compute the p-value. 
2 P-value boundary of 0.05 is used to conclude statistical significance. It is important to note that conclusions from 
DOOR analyses must rely on a detailed assessment of the DOOR components as well as consideration of sensitivity 
analyses, in addition to the statistical test described in this table. 
 


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Table 15: 
Primary ITT Analysis of DOOR at Outcome Assessment Visit #2 
Statistic 
Value 
Subjects with all DOOR components measured – n (%) 
x (x) 
Subjects with one or more DOOR components imputed – n (%) 
x (x) 
Pr(Higher DOOR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
P-value2 
x.xxx 
1 Probability of Higher DOOR in Short-Course Arm at Outcome Assessment Visit #2 + 0.5 Probability of Equal 
DOOR. Confidence interval obtained through inversion of the F-test used to compute the p-value. 
2 P-value boundary of 0.05 is used to conclude statistical significance. It is important to note that conclusions from 
DOOR analyses must rely on a detailed assessment of the DOOR components as well as consideration of sensitivity 
analyses, in addition to the statistical test described in this table. 
 


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Table 16: 
Sensitivity Analyses of DOOR at Outcome Assessment Visit #1 
Analysis 
Pr 
(Higher DOOR)1 
Normal Approx. 
95% CI2 
Bootstrapped 
95% CI3 
P-value4 
Complete Case (CC-V1) 
 
 
 
 
According-to-Protocol (ATP-V1) 
 
 
 
 
Worst Case (ITT) 
 
 
 
 
1 Probability of Higher DOOR in Short-Course Arm at Outcome Assessment Visit #1 + 0.5 Probability of Equal 
DOOR. 
2 Obtained through using inversion of the Mann-Whitney U test with a normal approximation and assuming the null 
hypothesis distribution variance Var(U)=n1n2(n1+n2+1)/12.  
3 2.5th and 97.5th percentiles of Pr (Higher DOOR) obtained by repeatedly re-sampling of the empirical 
distributions of DOOR scores by treatment arm. 
4 P-value obtained by Mann-Whitney U Test. 
 


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Table 17: 
Sensitivity Analyses of DOOR at Outcome Assessment Visit #2 
Analysis 
Pr 
(Higher DOOR)1 
Normal Approx. 
95% CI2 
Bootstrapped 
95% CI3 
P-value4 
Complete Case (CC-V2) 
 
 
 
 
According-to-Protocol (ATP-V2) 
 
 
 
 
Worst Case (ITT) 
 
 
 
 
1 Probability of Higher DOOR in Short-Course Arm at Outcome Assessment Visit #2 + 0.5 Probability of Equal 
DOOR. 
2 Obtained through using inversion of the Mann-Whitney U test with a normal approximation and assuming the null 
hypothesis distribution variance Var(U)=n1n2(n1+n2+1)/12. 
3 2.5th and 97.5th percentiles of Pr(Higher DOOR) obtained by repeatedly re-sampling of the empirical distributions 
of DOOR scores by treatment arm. 
4 P-value obtained by Mann-Whitney U Test. 
 


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Table 18: 
Risk of Mild, Moderate, or Severe Solicited Event from Day 1 to Day 5 (CC-
V1 Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Risk Difference 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Any Event 
 
 
 
 
 
 
 
 
 
Irritability 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
Allergic Reaction 
 
 
 
 
 
 
 
 
 
Stomatitis 
 
 
 
 
 
 
 
 
 
Candidiasis 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V1 analysis population and the respective treatment group 
with complete records of solicited events recorded from Day 1 to Day 5. 
1 P-value obtained by Fisher Exact Test. 
 


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Table 19: 
Risk of Moderate or Severe Solicited Event from Day 1 to Day 5 (CC-V1 
Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Risk Difference 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Any Event 
 
 
 
 
 
 
 
 
 
Irritability 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
Allergic Reaction 
 
 
 
 
 
 
 
 
 
Stomatitis 
 
 
 
 
 
 
 
 
 
Candidiasis 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V1 analysis population and the respective treatment group 
with complete records of solicited events recorded from Day 1 to Day 5. 
1 P-value obtained by Fisher Exact Test. 
 


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Table 20: 
Risk of Severe Solicited Event from Day 1 to Day 5 (CC-V1 Cohort) by 
Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Risk Difference 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Any Event 
 
 
 
 
 
 
 
 
 
Irritability 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
Allergic Reaction 
 
 
 
 
 
 
 
 
 
Stomatitis 
 
 
 
 
 
 
 
 
 
Candidiasis 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V1 analysis population and the respective treatment group 
with complete records of solicited events recorded from Day 1 to Day 5. 
1 P-value obtained by Fisher Exact Test. 
 


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Table 21: 
Risk of Mild, Moderate, or Severe Solicited Event from Day 1 to Day 18 (CC-
V2 Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Risk Difference 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Any Event 
 
 
 
 
 
 
 
 
 
Irritability 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
Allergic Reaction 
 
 
 
 
 
 
 
 
 
Stomatitis 
 
 
 
 
 
 
 
 
 
Candidiasis 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V2 analysis population and the respective treatment group 
with complete records of solicited events recorded from Day 1 to Day 18. 
1 P-value obtained by Fisher Exact Test. 
 


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Table 22: 
Risk of Moderate or Severe Solicited Event from Day 1 to Day 18 (CC-V2 
Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Risk Difference 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Any Event 
 
 
 
 
 
 
 
 
 
Irritability 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
Allergic Reaction 
 
 
 
 
 
 
 
 
 
Stomatitis 
 
 
 
 
 
 
 
 
 
Candidiasis 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V2 analysis population and the respective treatment group 
with complete records of solicited events recorded from Day 1 to Day 18. 
1 P-value obtained by Fisher Exact Test. 
 


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Table 23: 
Risk of Severe Solicited Event from Day 1 to Day 18 (CC-V2 Cohort) by 
Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Risk Difference 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Any Event 
 
 
 
 
 
 
 
 
 
Irritability 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
Allergic Reaction 
 
 
 
 
 
 
 
 
 
Stomatitis 
 
 
 
 
 
 
 
 
 
Candidiasis 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V2 analysis population and the respective treatment group 
with complete records of solicited events recorded from Day 1 to Day 18. 
1 P-value obtained by Fisher Exact Test. 
 


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Table 24: 
Lack of Resolution of Symptoms and Its Components at Outcome 
Assessment Visit #1 (CC-V1 Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Difference in 
Proportion 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Lack of Resolution of Symptoms 
 
 
 
 
 
 
 
 
 
Fever2 
 
 
 
 
 
 
 
 
 
Elevated respiratory rate3 
 
 
 
 
 
 
 
 
 
Cough4 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V1 analysis population and the respective treatment group 
with complete records of fever, elevated respiratory rate, and cough at Outcome Assessment Visit #1. 
1 P-value obtained by Fisher Exact Test. 
2 As defined in Section 6.5.2 of the SAP. 
3 Elevated respiratory rate (RR >50 breaths/minute for children <24 months of age and >40 breaths/minute for 
children 24-71 months of age) at the time of the Outcome Assessment Visit. 
4 Presence of cough Grade 2 or 3 at the Outcome Assessment Visit. 
 


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Table 25: 
Lack of Resolution of Symptoms and Its Components at Outcome 
Assessment Visit #2 (CC-V2 Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Difference in 
Proportion 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Lack of Resolution of Symptoms 
 
 
 
 
 
 
 
 
 
Fever2 
 
 
 
 
 
 
 
 
 
Elevated respiratory rate3 
 
 
 
 
 
 
 
 
 
Cough4 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V2 analysis population and the respective treatment group 
with complete records of fever, elevated respiratory rate, and cough at Outcome Assessment Visit #2. 
1 P-value obtained by Fisher Exact Test. 
2 As defined in Section 6.5.2 of the SAP. 
3 Elevated respiratory rate (RR >50 breaths/minute for children <24 months of age and >40 breaths/minute for 
children 24-71 months of age) at the time of the Outcome Assessment Visit. 
4 Presence of cough Grade 2 or 3 at the Outcome Assessment Visit. 
 


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Table 26: 
Risk of Lack of Adequate Clinical Response and Its Components from Day 1 
to Day 5 (CC-V1 Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Difference in 
Proportion 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Lack of Adequate Clinical Response 
 
 
 
 
 
 
 
 
 
ED or Clinic Visit2 
 
 
 
 
 
 
 
 
 
Hospitalization2 
 
 
 
 
 
 
 
 
 
Surgical Procedure3 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study Antibiotic4 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V1 analysis population. 
1 P-value obtained by Fisher Exact Test. 
2 For persistent or worsening pneumonia that occurs after randomization and receipt of at least one dose of study 
drug. 
3 For pneumonia or treatment for a complication of pneumonia, including but not limited to drainage of pleural fluid, 
placement of a chest tube, video assisted thoracoscopic surgery, or thoracotomy procedures. 
4 For pneumonia or treatment for a complication of pneumonia. Receipt of a non-study antibiotic will not be 
regarded as satisfying this definition if it is related to a new diagnosis that is unrelated to the prior diagnosis of 
pneumonia. 
 


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Table 27: 
Any Receipt of Non-Study Antibiotics and Medically Attended Visits from 
Day 1 to Day 5 (CC-V1 Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Difference in 
Proportion 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
ED or Clinic Visit2 
 
 
 
 
 
 
 
 
 
Hospitalization2 
 
 
 
 
 
 
 
 
 
Surgical Procedure2 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study Antibiotic2 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V1 analysis population. 
1 P-value obtained by Fisher Exact Test. 
2 For any reason. 
 


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Table 28: 
Risk of Lack of Adequate Clinical Response and Its Components from Day 1 
to Day 18 (CC-V2 Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Difference in 
Proportion 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
Lack of Adequate Clinical Response 
 
 
 
 
 
 
 
 
 
ED or Clinic Visit2 
 
 
 
 
 
 
 
 
 
Hospitalization2 
 
 
 
 
 
 
 
 
 
Surgical Procedure3 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study Antibiotic4 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V2 analysis population. 
1 P-value obtained by Fisher Exact Test. 
2 For persistent or worsening pneumonia that occurs after randomization and receipt of at least one dose of study 
drug. 
3 For pneumonia or treatment for a complication of pneumonia, including but not limited to drainage of pleural fluid, 
placement of a chest tube, video assisted thoracoscopic surgery, or thoracotomy procedures. 
4 For pneumonia or treatment for a complication of pneumonia. Receipt of a non-study antibiotic will not be 
regarded as satisfying this definition if it is related to a new diagnosis that is unrelated to the prior diagnosis of 
pneumonia. 
 


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Table 29: 
Any Receipt of Non-Study Antibiotics or Medically Attended Visit from Day 
1 to Day 18 (CC-V2 Cohort) by Treatment Group 
Event 
Standard Course 
(N=X) 
Short Course 
(N=X) 
Difference in 
Proportion 
P-value1 
n 
% 
95% CI 
n 
% 
95% CI 
% 
95% CI 
ED or Clinic Visit2 
 
 
 
 
 
 
 
 
 
Hospitalization2 
 
 
 
 
 
 
 
 
 
Surgical Procedure2 
 
 
 
 
 
 
 
 
 
Receipt of Non-Study Antibiotic2 
 
 
 
 
 
 
 
 
 
Note: N=X indicates the number of subjects in the CC-V2 analysis population. 
1 P-value obtained by Fisher Exact Test. 
2 For any reason. 
 


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Table 30: 
ITT Analysis of Ordinal Clinical Response at Outcome Assessment Visit #1 
Statistic 
Value 
Subjects with non-missing OCR– n (%) 
 
   Standard Course (N=X)  
x (x) 
   Short Course (N=X) 
x (x) 
Pr(Lower OCR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
P-value2 
x.xxx 
Non-inferiority3 
Yes/No 
1 Probability of Lower OCR in Short-Course Arm at Outcome Assessment Visit #1 + 0.5 Probability of Equal OCR. 
Confidence interval obtained through inversion of the F-test used to compute the p-value. In contrast to DOOR, 
lower OCRs are more favorable. 
2 Test of null hypothesis “Pr(OCR at Outcome Assessment Visit #1 is better in short-course) + 0.5 Pr(OCR at 
Outcome Assessment Visit #1 is equal) = 0.5”. P-value boundary of 0.05 is used to conclude statistical significance. 
3 Non-inferiority is concluded if the lower bound of the confidence interval for Pr(Lower OCR) is greater than 0.40. 
 


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Table 31: 
ITT Analysis of Ordinal Clinical Response at Outcome Assessment Visit #2 
Statistic 
Value 
Subjects with non-missing OCR– n (%) 
 
   Standard Course (N=X)  
x (x) 
   Short Course (N=X) 
x (x) 
Pr(Lower OCR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
P-value2 
x.xxx 
Non-inferiority3 
Yes/No 
1 Probability of Lower OCR in Short-Course Arm at Outcome Assessment Visit #2 + 0.5 Probability of Equal OCR.  
Confidence interval obtained through inversion of the F-test used to compute the p-value.  In contrast to DOOR, 
lower OCRs are more favorable. 
2 Test of null hypothesis “Pr(OCR at Outcome Assessment Visit #2 is better in short-course) + 0.5 Pr(OCR at 
Outcome Assessment Visit #2 is equal) = 0.5”.  P-value boundary of 0.05 is used to conclude statistical significance.  
3 Non-inferiority is concluded if the lower bound of the confidence interval for Pr(Lower OCR) is greater than 0.40. 
 


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Table 32: 
Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #1 (CC-V1) 
Statistic 
Value 
CC-V1 Subjects (N=X) 
 
   Standard Course – n (%) 
x (x) 
   Short Course – n (%) 
x (x) 
Pr(Lower OCR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
P-value2 
x.xxx 
Non-inferiority3 
Yes/No 
1 Probability of Lower OCR in Short-Course Arm at Outcome Assessment Visit #1 + 0.5 Probability of Equal OCR. 
Confidence interval obtained through inversion of the F-test used to compute the p-value. In contrast to DOOR, 
lower OCRs are more favorable. 
2 Test of null hypothesis “Pr(OCR at Outcome Assessment Visit #1 is better in short-course) + 0.5 Pr(OCR at 
Outcome Assessment Visit #1 is equal) = 0.5”. P-value boundary of 0.05 is used to conclude statistical significance. 
3 Non-inferiority is concluded if the lower bound of the confidence interval for Pr(Lower OCR) is greater than 0.40. 
 


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Table 33: 
Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #1 (CC-V1) - Comparison of Distributions 
 
Ordinal Clinical Response 
 
1 
2 
3 
4 
5 
6 
7 
8 
Standard Course (N=X) – n (%) 
 
 
 
 
 
 
 
 
Short Course (N=X) – n (%) 
 
 
 
 
 
 
 
 
Mean Score Statistic (QS) P-Value: x.xxx 
 


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Table 34: 
Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #2 (CC-V2) 
Statistic 
Value 
CC-V2 Subjects (N=X) 
 
   Standard Course – n (%) 
x (x) 
   Short Course – n (%) 
x (x) 
Pr(Lower OCR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
P-value2 
x.xxx 
Non-inferiority3 
Yes/No 
1 Probability of Lower OCR in Short-Course Arm at Outcome Assessment Visit #2 + 0.5 Probability of Equal OCR. 
Confidence interval obtained through inversion of the F-test used to compute the p-value. In contrast to DOOR, 
lower OCRs are more favorable. 
2 Test of null hypothesis “Pr(OCR at Outcome Assessment Visit #2 is better in short-course) + 0.5 Pr(OCR at 
Outcome Assessment Visit #2 is equal) = 0.5”. P-value boundary of 0.05 is used to conclude statistical 
significance. 
3 Non-inferiority is concluded if the lower bound of the confidence interval for Pr(Lower OCR) is greater than 0.40. 
 


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Table 35: 
Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #2 (CC-V2) - Comparison of Distributions 
 
Ordinal Clinical Response 
 
1 
2 
3 
4 
5 
6 
7 
8 
Standard Course (N=X) – n (%) 
 
 
 
 
 
 
 
 
Short Course (N=X) – n (%) 
 
 
 
 
 
 
 
 
Mean Score Statistic (QS) P-Value: x.xxx 
 


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Table 36: 
According-to-Protocol Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #1 (ATP-V1) 
Statistic 
Value 
ATP-V1 Subjects (N=X) 
 
   Standard Course – n (%) 
x (x) 
   Short Course – n (%) 
x (x) 
Pr(Lower OCR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
Test No Difference in OCR, P-value2 
x.xxx 
Non-inferiority3 
Yes/No 
1 Probability of Lower OCR in Short-Course Arm at Outcome Assessment Visit #1 + 0.5 Probability of Equal OCR. 
Confidence interval obtained through inversion of the F-test used to compute the p-value. In contrast to DOOR, 
lower OCRs are more favorable. 
2 Test of null hypothesis “Pr(OCR at Outcome Assessment Visit #1 is better in short-course) + 0.5 Pr(OCR at 
Outcome Assessment Visit #1 is equal) = 0.5”. P-value boundary of 0.05 is used to conclude statistical significance. 
3 Non-inferiority is concluded if the lower bound of the confidence interval for Pr(Lower OCR) is greater than 0.40. 
 


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Table 37: 
Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #1 (ATP-V1) - Comparison of Distributions 
 
Ordinal Clinical Response 
 
1 
2 
3 
4 
5 
6 
7 
8 
Standard Course (N=X) – n (%) 
 
 
 
 
 
 
 
 
Short Course (N=X) – n (%) 
 
 
 
 
 
 
 
 
Mean Score Statistic (QS) P-Value: x.xxx 
 


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Table 38: 
According-to-Protocol Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #2 (ATP-V2) 
Statistic 
Value 
ATP-V2 Subjects (N=X) 
 
   Standard Course – n (%) 
x (x) 
   Short Course – n (%) 
x (x) 
Pr(Lower OCR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
P-value2 
x.xxx 
Non-inferiority3 
Yes/No 
1 Probability of Lower OCR in Short-Course Arm at Outcome Assessment Visit #2 + 0.5 Probability of Equal OCR. 
Confidence interval obtained through inversion of the F-test used to compute the p-value. In contrast to DOOR, 
lower OCRs are more favorable. 
2 Test of null hypothesis “Pr(OCR at Outcome Assessment Visit #2 is better in short-course) + 0.5 Pr(OCR at 
Outcome Assessment Visit #2 is equal) = 0.5”. P-value boundary of 0.05 is used to conclude statistical significance. 
3 Non-inferiority is concluded if the lower bound of the confidence interval for Pr(Lower OCR) is greater than 0.40. 
 


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Table 39: 
Complete Case Analysis of Ordinal Clinical Response at Outcome 
Assessment Visit #2 (ATP-V2) - Comparison of Distributions 
 
Ordinal Clinical Response 
 
1 
2 
3 
4 
5 
6 
7 
8 
Standard Course (N=X) – n (%) 
 
 
 
 
 
 
 
 
Short Course (N=X) – n (%) 
 
 
 
 
 
 
 
 
Mean Score Statistic (QS) P-Value: x.xxx 
 


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Table 40: 
Worst Case Analysis of Ordinal Clinical Response at Outcome Assessment 
Visit #1 (ITT Cohort) 
Statistic 
Value 
Subjects with non-missing OCR– n (%) 
 
   Standard Course (N=X)  
x (x) 
   Short Course (N=X) 
x (x) 
Pr(Lower OCR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
Test No Difference in OCR, P-value2 
x.xxx 
Non-inferiority3 
Yes/No 
1 Probability of Lower OCR in Short-Course Arm at Outcome Assessment Visit #1 + 0.5 Probability of Equal OCR. 
Confidence interval obtained through inversion of the F-test used to compute the p-value. In contrast to DOOR, 
lower OCRs are more favorable. 
2 Test of null hypothesis “Pr(OCR at Outcome Assessment Visit #1 is better in short-course) + 0.5 Pr(OCR at 
Outcome Assessment Visit #1 is equal) = 0.5”. P-value boundary of 0.05 is used to conclude statistical significance. 
3 Non-inferiority is concluded if the lower bound of the confidence interval for Pr(Lower OCR) is greater than 0.40. 
 


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Table 41: 
Worst Case Analysis of Ordinal Clinical Response at Outcome Assessment 
Visit #2 (ITT Cohort) 
Statistic 
Value 
Subjects with non-missing OCR– n (%) 
 
   Standard Course (N=X)  
x (x) 
   Short Course (N=X) 
x (x) 
Pr(Lower OCR in Short-Course)1    (95% CI) 
x.x (x.x – x.x) 
P-value2 
x.xxx 
Non-inferiority3 
Yes/No 
1 Probability of Lower OCR in Short-Course Arm at Outcome Assessment Visit #2 + 0.5 Probability of Equal OCR. 
Confidence interval obtained through inversion of the F-test used to compute the p-value. In contrast to DOOR, 
lower OCRs are more favorable. 
2 Test of null hypothesis “Pr(OCR at Outcome Assessment Visit #2 is better in short-course) + 0.5 Pr(OCR at 
Outcome Assessment Visit #2 is equal) = 0.5”. P-value boundary of 0.05 is used to conclude statistical significance. 
3 Non-inferiority is concluded if the lower bound of the confidence interval for Pr(Lower OCR) is greater than 0.40. 
 


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Table 42: 
Number and Percentage of Subjects Experiencing Moderate or Severe Cough by Day and Treatment Group 
Study Day or Visit 
Standard Course - Moderate or Severe Cough 
Short Course - Moderate or Severe Cough 
N 
n 
% 
95% CI 
N 
n 
% 
95% CI 
Overall 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
OAV #1 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
OAV #2 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
Day 1 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
Day 2 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
Day 3 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
Day 4 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
Day 5 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
Days 6-9 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
Day 10-13 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
Day 14-18 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
Day 19-25 
x 
x 
x 
(x, x) 
x 
x 
x 
(x, x) 
N = Number of subjects in the Safety Analysis Population in the respective treatment group and with at least one severity grade collected for cough on the 
respective day or days. 
 


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Table 43: 
Number and Percentage of Subjects Experiencing Coughing by Maximum Severity and Treatment Group – 
Standard Course 
Severity 
Standard Course 
Day 1 
(N=X) 
n (%) 
Day 2 
(N=X) 
n (%) 
Day 3 
(N=X) 
n (%) 
Day 4 
(N=X) 
n (%) 
Day 5 
(N=X) 
n (%) 
Days 6-9 
(N=X) 
n (%) 
Days 10-13 
(N=X) 
n (%) 
Days 14-18 
(N=X) 
n (%) 
Days 19-25 
(N=X) 
n (%) 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
N = Number of subjects in the Safety Analysis Population in the respective treatment group and with at least one severity grade collected for cough on the 
respective day or days. 
 


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Table 44: 
Number and Percentage of Subjects Experiencing Coughing by Maximum Severity and Treatment Group – 
Short Course 
Severity 
Short Course 
Day 1 
(N=X) 
n (%) 
Day 2 
(N=X) 
n (%) 
Day 3 
(N=X) 
n (%) 
Day 4 
(N=X) 
n (%) 
Day 5 
(N=X) 
n (%) 
Days 6-9 
(N=X) 
n (%) 
Days 10-13 
(N=X) 
n (%) 
Days 14-18 
(N=X) 
n (%) 
Days 19-25 
(N=X) 
n (%) 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
N = Number of subjects in the Safety Analysis Population in the respective treatment group and with at least one severity grade collected for cough on the 
respective day or days. 
 


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Table 45: 
Number and Percentage of Subjects Experiencing Cough of Mild Severity or Greater, Moderate Severity or 
Greater, or Severe Severity Over the Follow-up Period by Treatment Group 
Severity 
Standard Course (N=X) 
Short Course (N=X) 
Odds Ratio (95% CI) 
P-Value 
n (%) 
95% CI 
n (%) 
95% CI 
 
 
Mild or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
Moderate or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
Severe 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
 


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Table 46: 
CC-V1 Evaluation of DOOR at Outcome Assessment Visit #1, Minimum 
Required Difference in Days for Antibiotic Use “Tie-Breaking” Varies 
k=1,2,3,4,5, or Infinity 
k 
Pr(Higher DOOR)1 
95% CI 
P-value 
1 
x.x 
(x.x – x.x) 
x.x 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
∞ 
 
 
 
1 Probability of Higher DOOR in Short-Course Arm at Outcome Assessment Visit #1 + 0.5 Probability of Equal 
DOOR 
 


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Table 47: 
ITT Evaluation of DOOR at Outcome Assessment Visit #1, Analysis By 
Stratification Variable and Clinical Site 
Variable 
Level 
Pr(Higher 
DOOR)1 
95% CI 
P-value 
Age (Months) 
<24 
x.x 
(x.x – x.x) 
x.x 
24-71 
 
 
 
Initial Site of Treatment 
ED 
 
 
 
Out-Patient / Urgent Care 
 
 
 
Initial Antibiotic 
Cefdinir 
 
 
 
Amoxicillin 
 
 
 
Amoxicillin Clavulanate 
 
 
 
Clinical Site 
Children’s Hospital of 
Philadelphia 
 
 
 
Children’s Hospital of Pittsburgh 
 
 
 
Cincinnati Children’s Hospital 
 
 
 
Duke University 
 
 
 
Vanderbilt University 
 
 
 
1 Probability of Higher DOOR in Short-Course Arm at Outcome Assessment Visit #1 + 0.5 Probability of Equal 
DOOR 
 
[Programming Note: Rows will be added for additional sites that enroll at least one subject, as 
needed.] 
 


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Table 48: 
As Treated Analysis of Association between Ordinal Clinical Response and 
the Number of Days of Antibiotic Use at Outcome Assessment Visit #1 and 
Outcome Assessment Visit #2 
Outcome Assessment Visit1 
Proportional Odds2 
Odds Ratio for 1 Additional 
Day of Antibiotic Use 
95% CI 
P-value 
#1 
x.xx 
(x.xx, x.xx) 
x.xxx 
#2 
x.xx 
(x.xx, x.xx) 
x.xxx 
1 Analysis at Outcome Assessment Visit #1 uses the subset of the CC-V1 analysis population that did not receive 
systemic antibiotic unrelated to pneumonia on or prior to Day 5. Analysis at Outcome Assessment Visit #2 uses the 
subset of the CC-V2 analysis population that did not receive systemic antibiotic unrelated to pneumonia on or prior 
to Day 18. 
2 Odds ratio of an OCR at Outcome Assessment Visit #1 greater than k for the effect of one additional day of use of 
antibiotic, where k is any observed OCR value (1, 2, 3, …) besides the highest observed value. 
 


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14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
14.3.1.1 
Solicited Adverse Events 
Table 49: 
Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence Intervals by Symptom, Dose, and 
Treatment Group - Standard Course 
Standard Course 
Symptom 
Day 1 
(N=X) 
Day 2 
(N=X) 
Day 3 
(N=X) 
Day 4 
(N=X) 
Day 5 
(N=X) 
Day 6-9 
(N=X) 
Day 10-13 
(N=X) 
Day 14-18 
(N=X) 
Day 19-25 
(N=X) 
Day 1-25 
(N=X) 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
Any 
Symptom 
x 
xx 
x.x, 
x.x 
x 
xx 
x.x, 
x.x 
x 
xx 
x.x, 
x.x 
x 
xx 
x.x, 
x.x 
x 
xx 
x.x, 
x.x 
x 
xx 
x.x, 
x.x 
x 
xx 
x.x, 
x.x 
x 
xx 
x.x, 
x.x 
x 
xx 
x.x, 
x.x 
x 
xx 
x.x, 
x.x 
Irritability 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allergic 
Reaction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stomatitis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Candidiasis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Analysis Population in the respective treatment group and with severity grades collected for each solicited symptom on the respective day or 
days. 
 
Table with similar format: 
 
Table 50: 
Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence Intervals by Symptom, Dose, and 
Treatment Group – Short Course 
 


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Table 51: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Maximum Severity, Dose, and 
Treatment Group – Standard Course 
Symptom 
Severity 
Standard Course 
Day 1 
(N=X) 
n (%) 
Day 2 
(N=X) 
n (%) 
Day 3 
(N=X) 
n (%) 
Day 4 
(N=X) 
n (%) 
Day 5 
(N=X) 
n (%) 
Days 6-9 
(N=X) 
n (%) 
Days 10-13 
(N=X) 
n (%) 
Days 14-18 
(N=X) 
n (%) 
Days 19-25 
(N=X) 
n (%) 
Irritability 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Vomiting 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Diarrhea 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Allergic Reaction 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Stomatitis 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 


Statistical Analysis Plan - DMID Protocol: 14-0079 
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Table 51: Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Maximum Severity, Dose, and Treatment 
Group – Standard Course (continued) 
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Symptom 
Severity 
Standard Course 
Day 1 
(N=X) 
n (%) 
Day 2 
(N=X) 
n (%) 
Day 3 
(N=X) 
n (%) 
Day 4 
(N=X) 
n (%) 
Day 5 
(N=X) 
n (%) 
Days 6-9 
(N=X) 
n (%) 
Days 10-13 
(N=X) 
n (%) 
Days 14-18 
(N=X) 
n (%) 
Days 19-25 
(N=X) 
n (%) 
Candidiasis 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
N = Number of subjects in the Safety Analysis Population in the respective treatment group and with severity grades collected for each solicited symptom on the 
respective day or days. 
 


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Table 52: 
Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Maximum Severity, Dose, and 
Treatment Group – Short Course 
Symptom 
Severity 
Short Course 
Day 1 
(N=X) 
n (%) 
Day 2 
(N=X) 
n (%) 
Day 3 
(N=X) 
n (%) 
Day 4 
(N=X) 
n (%) 
Day 5 
(N=X) 
n (%) 
Days 6-9 
(N=X) 
n (%) 
Days 10-13 
(N=X) 
n (%) 
Days 14-18 
(N=X) 
n (%) 
Days 19-25 
(N=X) 
n (%) 
Irritability 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Vomiting 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Diarrhea 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Allergic Reaction 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Stomatitis 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 


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Table 52: Number and Percentage of Subjects Experiencing Solicited Events by Symptom, Maximum Severity, Dose, and Treatment 
Group – Short Course (continued) 
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Symptom 
Severity 
Short Course 
Day 1 
(N=X) 
n (%) 
Day 2 
(N=X) 
n (%) 
Day 3 
(N=X) 
n (%) 
Day 4 
(N=X) 
n (%) 
Day 5 
(N=X) 
n (%) 
Days 6-9 
(N=X) 
n (%) 
Days 10-13 
(N=X) 
n (%) 
Days 14-18 
(N=X) 
n (%) 
Days 19-25 
(N=X) 
n (%) 
Candidiasis 
None 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Mild 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Moderate 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
 
Severe 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
N = Number of subjects in the Safety Analysis Population in the respective treatment group and with severity grades collected for each solicited symptom on the 
respective day or days. 
 


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Table 53: 
Number and Percentage of Subjects Experiencing Solicited Adverse Events of Mild Severity or Greater, 
Moderate Severity or Greater, or Severe Severity Over the Follow-up Period by Treatment Group 
Symptom 
Severity 
Standard Course (N=X) 
Short Course (N=X) 
Odds Ratio (95% CI) 
P-Value 
n (%) 
95% CI 
n (%) 
95% CI 
Any Symptom 
Mild or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Moderate or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Severe 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
Irritability 
Mild or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Moderate or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Severe 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
Vomiting 
Mild or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Moderate or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Severe 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
Diarrhea 
Mild or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Moderate or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Severe 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
Allergic Reaction 
Mild or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Moderate or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Severe 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
Stomatitis 
Mild or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Moderate or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Severe 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
Candidiasis 
Mild or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Moderate or Greater 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
  
Severe 
x (x) 
(x, x) 
x (x) 
(x, x) 
x.x (x.x, x.x) 
x.xxx 
 


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14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
Table 54: 
Listing of Serious Adverse Events 
Adverse 
Event 
Associated 
with Dose 
No. 
No. of 
Days Post 
Associated 
Dose 
(Duration) 
No. of 
Days 
Post 
Dose the 
Event 
Became 
Serious 
Reason 
Reported 
as an 
SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken 
with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Subject ID: , Treatment Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Subject ID: , Treatment Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


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14.3.3 Narratives of Deaths, Other Serious and Significant Adverse Events 
(not included in SAP, but this is a placeholder for the CSR) 
 


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14.3.4 Laboratory Data Over Time 
Not applicable 
 


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14.3.5 Displays of Laboratory Results 
Not applicable 
 


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14.3.6 Displays of Vital Signs 
Table 55: 
Summary of Vital Signs by Visit and Treatment Group 
 
Enrollment Visit 
Outcome Assessment Visit #1 
Outcome Assessment Visit #2 
 
Standard Course 
Control 
Standard Course 
Control 
Standard Course 
Control 
Temperature (°F) 
N 
xx 
xx 
xx 
xx 
xx 
xx 
 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Std 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
x 
x 
x 
x 
x 
x 
 
Min, Max 
xx,xx 
xx,xx 
xx,xx 
xx,xx 
xx,xx 
xx,xx 
Respiratory Rate (breaths/min.) 
N 
xx 
xx 
xx 
xx 
xx 
xx 
 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Std 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
x 
x 
x 
x 
x 
x 
 
Min, Max 
xx,xx 
xx,xx 
xx,xx 
xx,xx 
xx,xx 
xx,xx 
Pulse (beats/min.) 
N 
xx 
xx 
xx 
xx 
xx 
xx 
 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
 
Std 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
x 
x 
x 
x 
x 
x 
 
Min, Max 
xx,xx 
xx,xx 
xx,xx 
xx,xx 
xx,xx 
xx,xx 
 
 


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14.4 
Summary of Concomitant Medications 
Table 56: 
Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Treatment Group 
WHO Drug Code 
Level 1, Anatomic 
Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
Standard Course 
(N=X) 
Short Course 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes 
x 
xx 
x 
xx 
x 
xx 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
 
 
 
 
 
 
 
[ATC 2 - 1] 
 
 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
 
 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
 
 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
 
 
N=Number of subjects in the Safety population.   n=Number of subjects reporting taking at least one medication in 
the specific WHO Drug Class. 
 


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Table 57: 
Medically Attended Visits 
 
Day 1-5 
Day 6-18 
Standard Course 
n (%) 
(N=X) 
Short Course 
n (%) 
(N=X) 
Standard Course 
n (%) 
(N=X) 
Short Course 
n (%) 
(N=X) 
Emergency Department Visit1 
 
 
 
 
Primary Care Provider Visit1 
 
 
 
 
Study Physician Visit1 
 
 
 
 
Urgent Care Visit1 
 
 
 
 
Other Medically Attended Visit1 
 
 
 
 
Additional Antibiotic Received2 
 
 
 
 
Drainage of pleural fluid2 
 
 
 
 
Placement of a chest tube2 
 
 
 
 
Video assisted thoracoscopic surgery2 
 
 
 
 
Thoracotomy procedure2 
 
 
 
 
Any other surgical procedure2 
 
 
 
 
Hospitalization2 
 
 
 
 
1 Visit associated with worsening study pneumonia. 
2 For pneumonia or a complication of pneumonia. 
 


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APPENDIX 2.  FIGURE MOCK-UPS 
LIST OF FIGURES 
Figure 1: Schematic of the Study Design ........................................................................................8 
Figure 2: 
CONSORT Flow Diagram .......................................................................................120 
Figure 3: 
Forest Plot of Risk Difference of Solicited Events on Day 1-5 of Grade Mild, 
Moderate, or Severe - CC-V1 Population.................................................................121 
Figure 4: 
Forest Plot of Risk Difference of Solicited Events on Day 1-5 of Grade 
Moderate or Severe - CC-V1 Population ..................................................................122 
Figure 5: 
Forest Plot of Risk Difference of Solicited Events on Day 1-5 of Grade 
Severe - CC-V1 Population ......................................................................................123 
Figure 6: 
Forest Plot of Risk Difference of Solicited Events on Day 1-18 of Grade 
Mild, Moderate, or Severe - CC-V2 Population .......................................................124 
Figure 7: 
Forest Plot of Risk Difference of Solicited Events on Day 1-18 of Grade 
Moderate or Severe - CC-V2 Population ..................................................................125 
Figure 8: 
Forest Plot of Risk Difference of Solicited Events on Day 1-18 of Grade 
Severe - CC-V2 Population ......................................................................................126 
Figure 9: 
Forest Plot of Risk Difference of Lack of Resolution of Symptoms and Its 
Components - Outcome Assessment Visit #1 - CC-V1 Population .........................127 
Figure 10: Forest Plot of Risk Difference of Lack of Resolution of Symptoms and Its 
Components - Outcome Assessment Visit #2 - CC-V2 Population .........................128 
Figure 11: Forest Plot of Risk Difference of Lack of Adequate Clinical Response and 
Its Components - Outcome Assessment Visit #1 - CC-V1 Population ....................129 
Figure 12: Forest Plot of Risk Difference of Any Receipt of Non-Study Antibiotics or 
Medically Attended Visit - Outcome Assessment Visit #1 - CC-V1 
Population .................................................................................................................129 
Figure 13: Forest Plot of Risk Difference of Lack of Adequate Clinical Response and 
Its Components - Outcome Assessment Visit #2 - CC-V2 Population ....................130 
Figure 14: Forest Plot of Risk Difference of Any Receipt of Non-Study Antibiotics or 
Medically Attended Visit - Outcome Assessment Visit #2 - CC-V2 
Population .................................................................................................................130 
Figure 15: 95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #1 - ITT Analysis .............................131 
Figure 16: 95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #1 - CC-V1 Analysis ........................132 
Figure 17: 95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #1 - ATP-V1 Analysis ......................132 


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Figure 18: 95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #1 - Worst Case Analysis .................132 
Figure 19: 95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #2 - ITT Analysis .............................132 
Figure 20: 95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #2 - CC-V2 Analysis ........................132 
Figure 21: 95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #2 - ATP-V2 Analysis ......................132 
Figure 22: 95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #2 - Worst Case Analysis .................132 
Figure 23: C-V1 Evaluation of DOOR at Outcome Assessment Visit #1 - Minimum 
Required Difference in Days for Antibiotic Use “Tie-Breaking” Varies 
k=1,2,3,4,5, or Infinity ..............................................................................................133 
Figure 24: Maximum Severity of Solicited Adverse Events (by Symptom) .............................134 
 


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Figure 2: 
CONSORT Flow Diagram 
 
[Programming Note: Diagram will include breakdown by treatment arm and will add the 
'Eligible but not Enrolled' category under subjects screened.] 
 
 


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Figure 3: 
Forest Plot of Risk Difference of Solicited Events on Day 1-5 of Grade Mild, 
Moderate, or Severe - CC-V1 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 


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Figure 4: 
Forest Plot of Risk Difference of Solicited Events on Day 1-5 of Grade 
Moderate or Severe - CC-V1 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 


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Figure 5: 
Forest Plot of Risk Difference of Solicited Events on Day 1-5 of Grade Severe 
- CC-V1 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 
 


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Figure 6: 
Forest Plot of Risk Difference of Solicited Events on Day 1-18 of Grade Mild, 
Moderate, or Severe - CC-V2 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 


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Figure 7: 
Forest Plot of Risk Difference of Solicited Events on Day 1-18 of Grade 
Moderate or Severe - CC-V2 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 
 


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Figure 8: 
Forest Plot of Risk Difference of Solicited Events on Day 1-18 of Grade 
Severe - CC-V2 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 
 


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Figure 9: 
Forest Plot of Risk Difference of Lack of Resolution of Symptoms and Its 
Components - Outcome Assessment Visit #1 - CC-V1 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 
 


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Figure 10: 
Forest Plot of Risk Difference of Lack of Resolution of Symptoms and Its 
Components - Outcome Assessment Visit #2 - CC-V2 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 
 


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Figure 11: 
Forest Plot of Risk Difference of Lack of Adequate Clinical Response and Its 
Components - Outcome Assessment Visit #1 - CC-V1 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 
 
Figure 12: 
Forest Plot of Risk Difference of Any Receipt of Non-Study Antibiotics or 
Medically Attended Visit - Outcome Assessment Visit #1 - CC-V1 Population 
 
[Figure 12 will repeat Figure 11 without the No ACR confidence interval and will show 
confidence intervals for all events Day 1 – Day 5 (ED/Clinic Visit, Hospitalization, Surgical 
Procedure, and receipt of Non-Study Antibiotic) rather than only those satisfying the definition 
for lack of adequate clinical response.] 


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Figure 13: 
Forest Plot of Risk Difference of Lack of Adequate Clinical Response and Its 
Components - Outcome Assessment Visit #2 - CC-V2 Population 
 
Note: Positive risk difference indicates a higher proportion of short-course subjects experienced the event than 
standard-course subjects. 
 
 
Figure 14: 
Forest Plot of Risk Difference of Any Receipt of Non-Study Antibiotics or 
Medically Attended Visit - Outcome Assessment Visit #2 - CC-V2 Population 
 
[Figure 14 will repeat Figure 13 without the No ACR confidence interval and will show 
confidence intervals for all events Day 1 – Day 18 (ED/Clinic Visit, Hospitalization, Surgical 
Procedure, and receipt of Non-Study Antibiotic) rather than only those satisfying the definition 
for lack of adequate clinical response.] 


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Figure 15: 
95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #1 - ITT Analysis 
 
1  Plots the 95% confidence intervals of the difference in the probability Pr(OCR≤k | treatment=m), where 
k=1,2,3,4,5,6,7 and m=0,1, between the two treatment groups.  Note there can be no difference in Pr(OCR≤8 | 
treatment=m) since the probability is always 1 for each treatment arm, so only the first seven levels of the OCR are 
plotted. 


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Figures with similar format: 
Figure 16: 
95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #1 - CC-V1 Analysis 
Figure 17: 
95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #1 - ATP-V1 Analysis 
Figure 18: 
95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #1 - Worst Case Analysis 
Figure 19: 
95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #2 - ITT Analysis 
Figure 20: 
95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #2 - CC-V2 Analysis 
Figure 21: 
95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #2 - ATP-V2 Analysis 
Figure 22: 
95% Cumulative Difference Plot1 of Ordinal Clinical Response (OCR) by 
Treatment Arm - Outcome Assessment Visit #2 - Worst Case Analysis 
 


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Figure 23: 
C-V1 Evaluation of DOOR at Outcome Assessment Visit #1 - Minimum 
Required Difference in Days for Antibiotic Use “Tie-Breaking” Varies 
k=1,2,3,4,5, or Infinity 
 
 


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14.3.1.1 Solicited Adverse Events 
Figure 24: 
Maximum Severity of Solicited Adverse Events (by Symptom) 
 
 
[Programming Note: This figure will present maximum severity of solicited events separately by 
treatment group. The mockup is an example only. The actual figure will contain treatment groups 
and solicited events relevant to the 14-0079 protocol.] 
 


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14.3.5 
Displays of Laboratory Results 
Not applicable 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
LIST OF LISTINGS 
Listing 1: 16.2.1 - Early Terminations or Discontinued Subjects .............................................138 
Listing 2: 16.2.2.1 - Subject-Specific Protocol Deviations .......................................................139 
Listing 3: 16.2.2.2 - Non-Subject-Specific Protocol Deviations ..............................................140 
Listing 4: 16.2.3 - Subjects Excluded from Analysis Populations ............................................141 
Listing 5: 16.2.4.1 - Demographic Data ....................................................................................142 
Listing 6: 16.2.4.2 - Pre-Existing and Concurrent Medical Conditions ....................................143 
Listing 7: 16.2.5 - Treatment Compliance ................................................................................144 
Listing 8: 16.2.6 - Solicited Events ...........................................................................................145 
Listing 9: 16.2.7 - Serious Adverse Events ...............................................................................146 
Listing 10: 16.2.8.1 - Vital Signs ................................................................................................147 
Listing 11: 16.2.8.2 - Physical Assessment Findings..................................................................148 
Listing 12: 16.2.9 - Concomitant Medications ............................................................................149 
Listing 13: 16.2.10.1 - Medically Attended Visits - Standard Course ........................................150 
Listing 14: 16.2.10.2 - Medically Attended Visits - Short Course .............................................151 
Listing 15: 16.2.11.1 - Cough - Standard Course .......................................................................152 
Listing 16: 16.2.11.2 - Cough - Short Course .............................................................................153 
Listing 17: 16.2.12.1 - Presence of Fever in Previous 24 Hours - Standard Course ...................154 
Listing 18: 16.2.12.2 - Presence of Fever in Previous 24 Hours - Short Course ........................155 
Listing 19: 16.2.13 - Ordinal Clinical Response and DOOR, According to CC-V1 and 
CC-V2 Analyses1 ......................................................................................................156 
 


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16.1.6 Listing of Subjects Receiving Investigational Product 
(not included in SAP, but this is a placeholder for the CSR) 
 


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16.2 
Database Listings by Subject 
16.2.1 Discontinued Subjects 
Listing 1: 
16.2.1 - Early Terminations or Discontinued Subjects 
Treatment Group 
Subject ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.2 Protocol Deviations 
Listing 2: 
16.2.2.1 - Subject-Specific Protocol Deviations 
Treatment 
Group 
Subject ID DV Number 
Deviation 
Deviation 
Category 
Study 
Day 
Reason for 
Deviation 
Deviation 
Resulted in 
AE? 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 3: 
16.2.2.2 - Non-Subject-Specific Protocol Deviations 
Site 
Start Date  
Deviation 
End Date 
Reason for 
Deviation 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Category 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.3 Subjects Excluded from the Efficacy Analysis 
Listing 4: 
16.2.3 - Subjects Excluded from Analysis Populations 
Treatment Group 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason Subject Excluded 
 
 
[e.g., ITT, CC-V1, ATP-1] 
[e.g., ITT, CC-V2, ATP-2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis.  “No” indicates that no data were available for inclusion in the 
analysis. 
 


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16.2.4 Demographic Data 
Listing 5: 
16.2.4.1 - Demographic Data 
Treatment 
Group 
Subject ID 
Sex 
Initial 
Antibiotic 
Initial Site of 
Treatment 
Age at Enrollment 
(months) 
Ethnicity 
Race 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[Implementation Note: If a subject is multi-racial, in “Race” column, note “Multiple: (list races, separated by a comma).”] 
 


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Listing 6: 
16.2.4.2 - Pre-Existing and Concurrent Medical Conditions 
Treatment 
Group 
Subject 
ID 
MH 
Number 
Medical History 
Term 
Condition Start 
Day 
Condition End 
Day 
MedDRA System Organ 
Class 
MedDRA Preferred 
Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.5 Compliance and/or Drug Concentration Data (if available) 
Listing 7: 
16.2.5 - Treatment Compliance 
Treatment Group 
Subject ID  
Dose(s) Missed 
Extra Doses 
 
 
[1,2,3,4,5,6,7,8,9,10] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.6 Solicited Events 
Listing 8: 
16.2.6 - Solicited Events 
Treatment Group 
Subject ID 
Study Day 
Irritability 
Vomiting 
Diarrhea 
Allergic Reaction 
Stomatitis 
Candidiasis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.7 Serious Adverse Events 
Listing 9: 
16.2.7 - Serious Adverse Events 
Adverse 
Event 
Associated 
with Dose 
No. 
No. of 
Days Post 
Associated 
Dose 
(Duration) 
No. of 
Days 
Post 
Dose the 
Event 
Became 
Serious 
Reason 
Reported 
as an 
SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken 
with 
Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Subject ID: , Treatment Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Subject ID: , Treatment Group: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


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16.2.8 Vital Signs and Physical Exam Findings 
Listing 10: 
16.2.8.1 - Vital Signs 
Treatment Group 
Subject ID 
Visit Number 
Temperature (°F) 
Respiration Rate 
(breaths/min) 
Pulse (beats/min) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 11: 
16.2.8.2 - Physical Assessment Findings 
Treatment Group 
Subject ID 
Planned 
Study Day 
Actual Study 
Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; 
Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.9 
Concomitant Medications 
Listing 12: 
16.2.9 - Concomitant Medications 
Treatment 
Group 
Subject 
ID 
CM 
Number 
Medication 
Medication Start 
Day 
Medication End 
Day 
Indication 
Taken for an 
AE? 
(AE Number) 
Taken for a condition 
on Medical History? 
(MH Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.10 Medically Attended Visits 
Listing 13: 
16.2.10.1 - Medically Attended Visits - Standard Course 
Subject ID 
Visit Study Day 
Visit Type1 
Antibiotic1 
Surgery1 
Hospitalization1 
Hospital 
Admit Day 
Hospital 
Discharge Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Asterisk indicates the visit, antibiotic, surgery, or hospitalization were due to pneumonia or a complication of pneumonia. 
 


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Listing 14: 
16.2.10.2 - Medically Attended Visits - Short Course 
Subject ID 
Visit Study Day 
Visit Type1 
Antibiotic1 
Surgery1 
Hospitalization1 
Hospital 
Admit Day 
Hospital 
Discharge Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Asterisk indicates the visit, antibiotic, surgery, or hospitalization were due to pneumonia or a complication of pneumonia. 
 


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16.2.11 
Cough 
Listing 15: 
16.2.11.1 - Cough - Standard Course 
 
Cough Severity by Study Day or Visit 
Subject ID 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
OAV1#1 
OAV1#2 
ETV2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 OAV = Outcome Assessment Visit 
2 ETV = Early Termination Visit 
 


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Listing 16: 
16.2.11.2 - Cough - Short Course 
 
Cough Severity by Study Day or Visit 
Subject ID 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
OAV1#1 
OAV1#2 
ETV2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 OAV = Outcome Assessment Visit 
2 ETV = Early Termination Visit 
 


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16.2.12 
Presence of Fever in Previous 24 Hours 
Listing 17: 
16.2.12.1 - Presence of Fever in Previous 24 Hours - Standard Course 
Subject ID 
Outcome Assessment 
Visit #1 
Outcome Assessment 
Visit #2 
Early Termination Visit 
Fever1 
Unrelated2 
Fever1 
Unrelated2 
Fever1 
Unrelated2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Recorded oral, rectal, axillary, or tympanic temperature ≥38.3˚C (100.9˚F) 
2 Fever attributed to a process unrelated to the prior diagnosis of pneumonia 
 
[Programming Note: Listing programmed from ACRTEMP and ACRFEV only.] 
 


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Listing 18: 
16.2.12.2 - Presence of Fever in Previous 24 Hours - Short Course 
Subject ID 
Outcome Assessment 
Visit #1 
Outcome Assessment 
Visit #2 
Early Termination Visit 
Fever1 
Unrelated2 
Fever1 
Unrelated2 
Fever1 
Unrelated2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Recorded oral, rectal, axillary, or tympanic temperature ≥38.3˚C (100.9˚F) 
2 Fever attributed to a process unrelated to the prior diagnosis of pneumonia 
 


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16.2.13 
Ordinal Clinical Response and DOOR, According to CC-V1 and CC-V2 Analyses1 
Listing 19: 
16.2.13 - Ordinal Clinical Response and DOOR, According to CC-V1 and CC-V2 Analyses1 
Subject ID 
Treatment Group 
Outcome Assessment Visit #1 
Outcome Assessment Visit #2 
Ordinal 
Clinical 
Response 
Days of 
Antibiotic Use 
DOOR 
Ordinal 
Clinical 
Response 
Days of 
Antibiotic Use 
DOOR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Ordinal Clinical Response, Days of Antibiotic Use, and DOOR at Outcome Assessment Visits #1 and #2 are only listed for subjects that had the respective 
Outcome Assessment Visit (no imputed values are shown). 
 


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APPENDIX 4. NCA TEMPLATE 
See separate document, if applicable.