Efficacy of Antibiotics in Children With Acute Sinusitis: Which Subgroups Benefit?
Phase: PHASE3
Conditions: Sinusitis, Respiratory Tract Infections
Sponsor: Nader Shaikh

DMID 15-0048 
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Efficacy of Antibiotics in Children with Acute Sinusitis: Which Subgroups Benefit? 
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Efficacy of Antibiotics in Children with Acute Sinusitis: Which Subgroups Benefit? 
 
DMID Protocol Number: 15-0048 
NCT Number: NCT02554383 
DMID Funding Mechanism: U01AI118506 
IND Sponsor: University of Pittsburgh 
Principal Investigators: Nader Shaikh, MD; Ellen R. Wald, MD 
DMID Program Officer & Scientific Lead: Kristina T. Lu, PhD 
DMID Medical Officer: Francisco Leyva  
DMID Medical Monitor: Mo Elsafy 
DMID Clinical Project Manager: Wendy Buchanan, BSN, MS 
Version Number: 11.0 
-2 November 2021 
 

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STATEMENT OF COMPLIANCE 
This trial will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following:  
• United States (US) 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 Council for 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; 
• Approved protocol. 
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 US federal regulations and ICH guidelines. 
 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name: Nader Shaikh, MD 
 
Title: Co-Principal Investigator 
 
 
 
 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name: Ellen Wald, MD 
 
Title: Co-Principal Investigator 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
Page 
Statement of Compliance 
 
 
 
 
 
 
 
 
Signature Page 
 
 
 
 
 
 
 
 
 
List of Abbreviations  
 
 
 
 
 
 
 
 
 
Protocol Summary 
 
 
 
 
 
 
 
 
 
 
1 
Key Roles .............................................................................................................................. 13 
2 
Background Information and Scientific Rationale ................................................................. 15 
2.1 
Background Information .......................................................................................... 15 
2.1.1 
Sinusitis ...................................................................................................... 15 
2.1.2 
Antimicrobial therapy .................................................................................. 15 
2.1.3 
Preliminary studies ..................................................................................... 15 
2.2 
Scientific Rationale ................................................................................................. 19 
2.2.1 
Rationale for the trial .................................................................................. 19 
2.2.2 
Rationale for using NP colonization to identify the subgroups ................... 21 
2.2.3 
Rationale for using colored nasal discharge to define subgroups .............. 21 
2.2.4 
Rationale for placebo ................................................................................. 22 
2.2.5 
Rationale for the use of clavulanate ........................................................... 22 
2.2.6 
Rationale for using the high-dose amoxicillin-clavulanate potassium ........ 22 
2.3 
Potential Risks and Benefits ................................................................................... 23 
2.3.1 
Potential Risks ............................................................................................ 23 
2.3.2 
Known Potential Benefits ........................................................................... 24 
3 
Objectives ............................................................................................................................. 26 
3.1 
Study Objectives ..................................................................................................... 26 
3.2 
Study Outcome Measures ...................................................................................... 26 
3.2.1 
Primary Outcome Measures ....................................................................... 26 
3.2.2 
Secondary Outcome Measures .................................................................. 26 
3.2.3 
Tertiary outcomes ....................................................................................... 27 
4 
Study Design ......................................................................................................................... 28 
5 
Study Enrollment and Withdrawal ......................................................................................... 30 
5.1 
Subject Inclusion Criteria ........................................................................................ 30 
5.2 
Subject Exclusion Criteria ....................................................................................... 30 
5.3 
Treatment Assignment Procedures ........................................................................ 30 
5.3.1 
Randomization Procedures ........................................................................ 30 
5.3.2 
Reasons for Withdrawal ............................................................................. 31 
5.3.3 
Handling of Withdrawals ............................................................................. 31 
5.3.4 
Termination of Study .................................................................................. 32 
6 
Study Intervention/Investigational Product ............................................................................ 33 
6.1 
Study Product Description ...................................................................................... 33 
6.1.1 
Acquisition .................................................................................................. 33 
6.1.2 
Formulation, Packaging, and Labeling ....................................................... 33 
6.1.3 
Product Storage and Stability ..................................................................... 33 

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6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................... 33 
6.3 
Modification of Study Intervention/Investigational Product for a Participant ........... 34 
6.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) .... 34 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ................................................................................................................... 35 
6.6 
Concomitant Medications/Treatments .................................................................... 35 
7 
Study Schedule ..................................................................................................................... 36 
7.1 
Screening – Day 1 .................................................................................................. 36 
7.2 
Enrollment/Baseline Visit (Entry Visit) – Day 1 ....................................................... 36 
7.3 
Follow-up eVisits – Days 2-11 ................................................................................ 37 
7.4 
Final Study Visit (End-of-Study Follow-up Visit) – Days 12 to 18 ........................... 37 
7.5 
Unscheduled Visit (Interim (Sick) Visit) ................................................................... 38 
8 
Study Procedures/Evaluations .............................................................................................. 39 
8.1 
Clinical Evaluations ................................................................................................. 39 
8.2 
Laboratory Evaluations ........................................................................................... 39 
8.2.1 
Clinical Laboratory Evaluations .................................................................. 39 
8.2.2 
Special Assays or Procedures ................................................................... 40 
8.2.3 
Specimen Preparation, Handling, and Shipping ......................................... 40 
9 
Assessment of Safety ........................................................................................................... 42 
9.1 
Specification of Safety Parameters ......................................................................... 42 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ............................................................................................................. 42 
9.2.1 
Adverse Events .......................................................................................... 42 
9.2.2 
Reactogenicity ............................................................................................ 44 
9.2.3 
Serious Adverse Events ............................................................................. 44 
9.2.4 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings ......................................................... 45 
9.3 
Reporting Procedures ............................................................................................. 45 
9.3.1 
Serious Adverse Events ............................................................................. 45 
9.3.2 
Regulatory Reporting for Studies Conducted Under IND ........................... 46 
9.3.3 
Reporting of Pregnancy .............................................................................. 46 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events ......................... 47 
9.5 
Halting Rules ........................................................................................................... 47 
9.6 
Safety Oversight (ISM plus DSMB) ......................................................................... 47 
10 Clinical Monitoring ................................................................................................................. 50 
10.1 
Site Monitoring Plan ................................................................................................ 50 
11 Statistical Considerations ...................................................................................................... 51 
11.1 
Study Hypotheses ................................................................................................... 51 
11.2 
Primary and Secondary Analyses ........................................................................... 51 
11.3 
Analysis Populations ............................................................................................... 51 
11.3.1 Intent-to-Treat Population (ITT) .................................................................. 51 
11.3.2 Per Protocol Population .............................................................................. 51 

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11.4 
Efficacy Assessments ............................................................................................. 51 
11.4.1 Primary Efficacy Variable ........................................................................... 52 
11.4.2 Secondary Efficacy Variables ..................................................................... 52 
11.5 
Safety and Tolerability Assessments ...................................................................... 52 
11.6 
Statistical Analyses ................................................................................................. 53 
11.6.1 General Considerations .............................................................................. 53 
11.6.2 Interim Analysis .......................................................................................... 53 
11.6.3 Subject Disposition ..................................................................................... 53 
11.6.4 Baseline (Pre-Treatment) Analyses ........................................................... 54 
11.6.5 Concomitant Medication Use ...................................................................... 54 
11.7 
Efficacy Analyses .................................................................................................... 54 
11.7.1 Primary Efficacy Analysis of the Primary Efficacy Endpoint ....................... 54 
11.7.2 Secondary Efficacy Analysis of the Primary Efficacy Endpoint .................. 54 
11.7.3 Secondary Efficacy Analyses of the Secondary Endpoints ........................ 55 
11.8 
Missing Data ........................................................................................................... 55 
11.9 
Handling of Data from Withdrawn Subjects ............................................................ 55 
11.10 Safety and Tolerability Analyses ............................................................................. 55 
11.10.1 
Compliance ..................................................................................... 55 
11.10.2 
Adverse Events .............................................................................. 55 
11.10.3 
Resource utilization ........................................................................ 56 
11.11 Sample Size Justification ........................................................................................ 56 
12 Source Documents and Access to Source Data/Documents ................................................ 57 
13 Quality Control and Quality Assurance ................................................................................. 58 
14 Ethics/Protection of Human Subjects .................................................................................... 59 
14.1 
Ethical Standard ...................................................................................................... 59 
14.2 
Institutional Review Board ...................................................................................... 59 
14.3 
Informed Consent Process ..................................................................................... 59 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 60 
14.5 
Subject Confidentiality ............................................................................................ 61 
14.6 
Costs, Subject Compensation, and Research Related Injuries .............................. 63 
14.7 
Study Discontinuation ............................................................................................. 64 
14.8 
Future Use of Stored Specimens ............................................................................ 64 
15 Data Handling and Record Keeping ..................................................................................... 65 
15.1 
Data Management Responsibilities ........................................................................ 65 
15.2 
Data Capture Methods ............................................................................................ 65 
15.3 
Timing/Reports ........................................................................................................ 66 
15.4 
Study Records Retention ........................................................................................ 67 
15.5 
Protocol Deviations ................................................................................................. 67 
16 Publication Policy .................................................................................................................. 68 
17 Literature cited ...................................................................................................................... 69 
18 SupplementS ........................................................................................................................ 74 
18.1 
Supplement A: Schedule of Events ........................................................................ 74 
18.2 
Supplement B: Pediatric Rhinosinusitis Symptom Scale (PRSS) ........................... 75 

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LIST OF ABBREVIATIONS 
AAP 
American Academy of Pediatrics 
AE 
Adverse Event 
AOM 
Acute Otitis Media 
CFR  
Code of Federal Regulations 
CRHC 
University of Pittsburgh Center for Research on Health Care 
CHP of UPMC 
Children’s Hospital of Pittsburgh at the University of Pittsburgh 
Medical Center 
CLSI 
Clinical Laboratory Standards Institute 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
DMSU 
Data Management and Statistical Unit in the Division of General 
Academic Pediatrics at the Children’s Hospital of Pittsburgh 
DHHS  
Department of Health and Human Services 
DMID  
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS  
DSMB  
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EHR 
Electronic Health Record 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equations 
H. influenzae 
Haemophilus influenzae 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH  
International Coucil for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IDS 
University of Pittsburgh Medical Center Investigational Drug 
Service 
IDSA 
Infectious Diseases Society of America 
IRB 
Institutional Review Board  
ISM 
Independent Safety Monitor 
IT 
Information Technology 
M. catarrhalis 
Moraxella catarrhalis 
KPAR 
Kentucky Pediatric/Adult Research 
KY 
Kentucky 
MOP 
MT 
Manual of Procedures 
Mid-Turbinate  
N 
Number (refers to number of subjects) 

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NIAID  
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH  
National Institutes of Health 
NLM 
National Library of Medicine 
NNT 
Number Needed to Treat 
NP 
Nasopharyngeal 
OHRP 
Office for Human Research Protections 
PA 
Pennsylvania 
PC 
Personal Computer 
PCP 
Primary Care Provider 
PCV-13 
Pneumococcal Conjugate 13-valent vaccine 
PI 
Principal Investigator 
PittNet PBRN 
PittNet Pediatric Practice Based Research Network 
PRSS 
Pediatric Rhinosinusitis Symptom Scale 
QA 
Quality Assurance 
QC 
Quality Control 
S. pneumoniae 
Streptococcus pneumoniae 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SPA 
Study Product Administrator 
URI 
Upper Respiratory Infection 
US 
United States 
WI 
 
Wisconsin 
 
 
 
 

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PROTOCOL SUMMARY 
Title: 
Efficacy of Antibiotics in Children with Acute Sinusitis: Which Subgroups Benefit? 
Phase: 
III 
Objectives: 
 
Primary 
• 
To determine whether the effect of antimicrobial treatment differs in predefined 
subgroups of children with acute sinusitis (i.e., to test for treatment subgroup 
interactions). Subgroups will be defined by the (1) presence vs. absence of 
nasopharyngeal (NP) colonization with respiratory pathogens (Streptococcus 
pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis), and (2) 
presence vs. absence of colored (yellow or green) nasal discharge. 
Secondary 
• 
To determine whether antimicrobial therapy is superior to placebo (i.e., to test for 
the overall effect).  
Tertiary 
• 
To evaluate compliance with study product. 
• 
To assess adverse events associated with use of amoxicillin clavulanate, 
including the development of bacterial resistance.  
• 
To compare resource utilization according to treatment strategy. 
 
Population: 
688 children aged 2 to 12 years, who meet the current AAP criteria for sinusitis. 
Inclusion 
Criteria: 
2 -12 years of age (before 12th birthday);Persistent sinusitis: URI symptoms present for 
>10 days without improvement (11-30 days); Worsening sinusitis: URI symptoms 
worsening after a period of improvement (6-10 days); baseline score ≥9 on the Pediatric 
Rhinosinusitis Symptom Scale (PRSS), ≥2 doses of pneumococcal conjugate vaccine or 
appropriate for age. 
Exclusion 
Criteria: 
Sinusitis with severe presentation (≥3 days of colored nasal discharge and fever ≥39˚ C); 
asthma/allergic rhinitis explains symptoms; allergy to amoxicillin-clavulanate; immotile 
cilia syndrome; cystic fibrosis; immunodeficiency; parental/legal guardian inability to 
read/write English or Spanish; other concurrent infection (e.g., pneumonia, acute otitis 
media, streptococcal pharyngitis); systemic toxicity; wheezing on exam; antibiotic use 
within 15 days; prior sinus surgery;  
Number of 
Sites: 
5 sites (Pittsburgh will enroll 388 children, and Bardstown, and Madison will enroll 100 
children each).. At each site, patients will be enrolled from primary care clinics. 
Availability of 
Subjects: 
Based on the preliminary data presented, we will be able to recruit at least 100 patients 
per year in Pittsburgh alone. Likewise, based on the strong track record of enrollment in 
clinical trials, other sites will be able to recruit at least 25 patients per year during the 
course of the study. 
Consent 
Process: 
Parents/legal guardians of children who meet criteria for persistent or worsening 
presentations of acute sinusitis will be approached for informed consent. Assent will be 
sought from older children who are believed to be developmentally capable. 

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Retention and 
Follow-up: 
In a preliminary study, our retention rate was 94%. In this study, we have built in 
additional measures to improve retention (electronic daily diary, phone calls to patients 
with missing data, reimbursement for completing the diary, and home visits). We 
anticipate no changes in the approaches for retention during the course of the trial. 
Study 
Duration: 
5 years 
Subject 
Duration: 
12 to 18 days 
Description of 
Agent and 
Rationale: 
Amoxicillin-clavulanate (90/6.4 mg/kg/d in 2 divided doses for 10 days) or matching 
placebo will be used. Amoxicillin-clavulanate was chosen because of the increasing 
prevalence of H. influenzae in nasopharyngeal specimens of children with bacterial 
respiratory infections, and because it is the most effective available orally administered 
antimicrobial drug against the respiratory pathogens most commonly causing sinusitis. A 
high dose of amoxicillin will minimize the number of children experiencing treatment 
failure in the active treatment group. The use of an agent with suboptimal antibacterial 
coverage would also make it more difficult to determine whether treatment effect 
heterogeneity exists. Ten days was chosen because this is the duration most frequently 
used in practice. 
Description of 
Study Design: 
Design: Multicenter, randomized, double-blind, placebo-controlled, parallel group trial 
Stratification variables: presence/absence of colored (yellow or green) nasal discharge 
and site of enrollment 
Duration of treatment: 10 days 
Primary outcome measure: Pediatric Rhinosinusitis Symptom Scale (PRSS). The 
PRSS will be administered every evening as an electronic diary. PRSS scores on Days 1 
to 11 will be the primary analysis variable (i.e., repeated measures over time will be used 
to measure disease burden). 
Secondary efficacy outcome measures: 
1) Treatment failure will be defined as follows: 
a. Worsening at any time–PRSS score increased by >20% from entry. 
b. No change by 48 hours–PRSS score decreased by <2 points from entry (Day 
1) to Day 3. 
c. Failure to improve significantly by 72 hours–PRSS score decreased by <20% 
from entry (Day 1) to Day 4. 
d. PRSS decreased by <20% from enrollment on 2 consecutive occasions on 
Days 5-11 
e. Still symptomatic (PRSS score ≥50% of entry score) at the time of the end-of-
study follow-up visit (Days 12 to 18). 
2) Development of AOM on Days 1 to 11. 
3) Receipt of a systemic antibiotic on Days 1 to 11 for any indication. 
Tertiary outcome measures: 

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1) Proportion with adverse events (including emergence of bacterial resistance). 
2) Proportion who are compliant with study product (took ≥70% of the doses). 
Flow of patients: We will review each child’s PRSS scores every morning and will 
contact parents/legal guardians of children whose PRSS scores are not improving at the 
expected rate (see definition of treatment failure above). These children will be seen by 
the study team and rescue medication will be prescribed, as clinically indicated and 
without breaking the blind, but they will be continued to be followed in the same way 
(electronic daily diary and routine end-of-study follow-up visit). 
Statistical methods:  
The primary efficacy analyses will be: 
• 
To determine whether the effect of treatment differs in children with and without 
nasopharyngeal colonization with respiratory pathogens (i.e., we will test for 
interaction). 
• 
To determine whether the effect of treatment differs in children with and without 
colored nasal discharge (i.e., we will test for interaction). 
Generalized estimating equations will be used for these analyses. The primary analysis 
will be based on the intention-to-treat principle and will use two-sided tests. The 
variables chosen to define the subgroups were based on extensive preliminary data 
indicating likely heterogeneity of treatment effect in subpopulations defined by the 
presence/absence of these variables. This sample size will allow us to test these 2 
hypotheses simultaneously. 
Laboratory 
Tests: 
A nasopharyngeal swab (or mid-turbinate nasal swab if a nasalpharyngeal swab is 
unable to be obtained)will be obtained at the baseline and final visit from all participants, 
when possible We will use the presence of respiratory pathogens as one of the 
subgrouping variables. These swabs will be shipped to the Microbiology Lab at the 
Children’s Hospital of Pittsburgh (CHP) on ice within 48 hours. According to the 
preliminary data presented, shipping of swabs does not adversely affect the ability to 
recover the respiratory pathogens being investigated. The Microbiology Lab will identify 
S. pneumoniae, H. influenzae, and M. catarrhalis using standard microbiological 
techniques. 
Data 
Management 
and 
Monitoring 
Plan: 
Data will be electronically captured using (21 CFR Part 11-compliant) electronic case 
report forms designed by the University of Pittsburgh Center for Research on Health 
Care (CRHC). Data will be saved on the secured CRHC servers which are backed-up 
daily and archived weekly. Quality and completeness of data collection will be monitored 
on an ongoing basis by the data manager at the Data Management and Statistical Unit in 
the Division of General Academic Pediatrics at the Children’s Hospital of Pittsburgh 
(DMSU). Independent clinical study site monitoring will be conducted as detailed in the 
clinical monitoring plan. 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 compliance.  
Time to 
Complete 
Enrollment: 
4.5 years 

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Schematic of Study Design: 
 
 
 
Enrollment Visit
● Written informed consent
● Nasopharyngeal specimen
● PRSS
● Stratification 
● Assessment of face and nose
N= 688
Study Entry
Day 1
Randomize
Amoxicillin Clavulanate  (10 days, high dose)
N= 344
Placebo
N= 344
Electronic diary every evening to assess:
● Improvement or deterioration of the PRSS score
● Adverse events
● Compliance with study product
Daily 
End-of-therapy 
Day 12-18
Assessment for final study outcomes
N = 688
End-of-study visit
● Review interim history 
● PRSS
● Review concomitant medications
● Collect study product
                  ● Nasopharyngeal specimen
Interim visit may occur at 
any time if worsening

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1 
KEY ROLES 
Individuals: 
 
DMID Program Officer & Scientific Lead: 
Kristina T. Lu, PhD 
 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
5601 Fishers Lane, Room 8E35, MSC 9825 
Bethesda, MD 20892-9825 
Work: 240-627-3307 
Email: kristina.lu@nih.gov 
 
DMID Clinical Project Manager: 
Wendy Buchanan, BSN, MS 
Division of Microbiology and Infectious Diseases 
NIAID, NIH 
5601 Fishers Lane, Room 8E38, MSC 9825 
Bethesda, MD 20892-9825 
Work: 240-292-4135 
Email: buchanaw@mail.nih.gov 
 
DMID Medical Officer: 
Francisco Leyva Division of Microbiology and Infectious 
Diseases 
NIAID, NIH 
5601 Fishers Lane, Room 8E25, MSC 9825 
Bethesda, MD 20892-9826 
Work: 301-761-7736 
Email: francisco.leyva@nih.gov  
 
DMID Medical Monitor: 
Mo Elsafy Division of Microbiology and Infectious Diseases 
NIAID, NIH 
5601 Fishers Lane, Room 7E59, MSC 9826 
Bethesda, MD 20892-9826 
Work: 240-292-4178 
Email: mohamed.elsafy@nih.gov 
 
Principal Investigators: 
Nader Shaikh, MPH, MD 
Associate Professor of Pediatrics 
University of Pittsburgh School of Medicine 
Division of General Academic Pediatrics 
CHP of UPMC, CHOB 3rd Floor, Suite 301 

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4401 Penn Avenue; Pittsburgh, PA 15224 
Phone: 412-692-8111 
Fax: 412-692-5807 
Email: nader.shaikh@chp.edu 
 
Ellen R. Wald, MD 
Professor and Chair, Department of Pediatrics 
University of Wisconsin, American Family Children’s Hospital 
600 Highland Avenue 
Madison, WI 53792 
Phone: 608-263-8558 
Fax: 608-265-3397 
Email: erwald@wisc.edu 
 
 
Institutions: 
 
CHP of UPMC 
4401 Penn Avenue 
Pittsburgh, PA 15224 
 
KPAR 
201 S Fifth St 
Bardstown, KY 40004 
 
American Family Children’s Hospital 
600 Highland Avenue 
Madison, WI 53792 
 
Cyn3rgy Research 
24850 SE Stark St. 
Bldg. 2, suite 180 
Gresham, OR 97030 
 
 
Please refer to the protocol-specific communication plan in the 
Manual of Procedures (MOP) for other contact information. 
 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
2.1.1 Sinusitis 
The current clinical practice guideline from the American Academy of Pediatrics for the 
Diagnosis and Management of Acute Bacterial Sinusitis recommends that the diagnosis of 
acute sinusitis is made when symptoms of an upper respiratory infection (URI) persist beyond 
10 days without showing signs of improvement (persistent presentation), when symptoms 
appear to worsen (on the 6th to 10th day) after a period of improvement (worsening 
presentation), or when both high fever and purulent nasal discharge are present concurrently for 
at least 3 consecutive days (severe presentation).1 In studies to date, children with persistent 
and worsening presentations comprise >95% of cases.2 Our preliminary data and the available 
literature suggest that only a subset of children being diagnosed with acute sinusitis on the 
basis of current criteria are likely to have bacterial disease. This is not entirely surprising 
because current criteria rely solely on the duration and the quality of respiratory tract symptoms 
(which are both common and non-specific). Accordingly, it seems likely that many children 
currently being diagnosed as having acute sinusitis actually have an uncomplicated URI. This is 
important because acute sinusitis is one of the most common diagnoses for which 
antimicrobials are prescribed for children in the US, accounting for 7.9 million prescriptions 
annually.3 A critical need thus exists to establish which children, if any, actually benefit from 
antimicrobial therapy. 
 
2.1.2 Antimicrobial therapy  
Inappropriate use of antibiotics contributes to the emergence of bacterial resistance on both 
individual and population levels.3 Sinusitis is the 5th most common reason for an antibiotic 
prescription for children in the US,4 and in contrast with most other frequently occurring pediatric 
infections, antibiotic prescribing rates for children with acute sinusitis have not decreased in the 
last 15 years.3 Yet, available literature and our preliminary data suggest that only a subset of 
children diagnosed as having acute sinusitis based on the current clinical criteria are likely to 
have bacterial disease. This is not entirely surprising because current criteria1 rely solely on the 
duration and the quality of respiratory tract symptoms. Because of the large overlap between 
symptoms of a viral upper respiratory tract infection (URI) and acute sinusitis, current criteria are 
insufficiently specific to identify children most likely to have bacterial disease. 
 
2.1.3 Preliminary studies 
In preparation for this trial, we prospectively enrolled 276 consecutive children aged 2 to 12 
years with persistent or worsening presentations of acute sinusitis from 6 outpatient clinics in 
Pittsburgh (NIH R21AI076677, N. Shaikh, PI). The aims of this observational study were to (1) 
develop and validate a symptom severity scale; (2) identify important prognostic factors that 
could be used to define subgroups in the present study; and (3) determine signs and symptoms 
associated with likely bacterial sinusitis, which could then be used to define subgroups for the 
present study. We screened 2023 children with URI symptoms for eligibility. A total of 355 (18%) 

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children met clinical criteria for the diagnosis of persistent or worsening presentations of acute 
sinusitis, and parents/legal guardians of 276 children agreed to enroll their children in our 
observational study. The mean age (standard deviation) of children enrolled was 6.4 (2.9) years. 
Almost all children (n=267) had sinus radiographs performed on the day of diagnosis and most 
(n=204) had a nasopharyngeal swab collected for bacterial culture (for reasons explained 
below). A large majority of children received antimicrobial therapy (n=227). Seventy six percent 
of children had abnormal sinus radiographs and 49% had pathogens (S. pneumoniae, H. 
influenzae, or M. catarrhalis) isolated from their nasopharynx.25-27 
 
          Development and validation of the Pediatric Rhinosinusitis Scale (PRSS). Development of 
the pilot version of the scale was based on well-established methods of scale development.28-30 
Detailed semi-structured interviews with children with acute sinusitis and their parents/legal 
guardians guided us in the selection of items most important to them. Based on these data, we 
selected, from a larger pool of items, 10 items for the pilot version of the scale. Each item on the 
pilot version of the scale was rated on a 3-point Likert scale (none = 0, a little = 1, a lot = 2) and 
the total score was obtained by summing the scores on 10 equally-weighted questions. The 276 
parents/legal guardians of children enrolled in the preliminary study were asked to complete the 
pilot version of the scale as a once-a-day paper diary (in the evening) for 8 to 10 days (i.e., from 
enrollment to the end-of-study follow-up visit). Two items (headache, fever) in the pilot version 
proved to have poor psychometric properties and were therefore dropped. Table 1 summarizes 
the psychometric properties of the remaining 8-item scale. These data support the validity and 
responsiveness of the PRSS; the scale appears to effectively measure severity of symptoms and 
overall functional status in young children with acute sinusitis. Changes in score over the first few 
days of illness were substantial and generally matched the assessments both of parents/legal 
guardians and of clinicians. 
  
Table 1. Psychometric properties of the PRSS scale  
Scale Property 
Measurement  
Result (Interpretation) 
Missing Data 
% scales with missing data  
2% had missing data (acceptable) 
Test-retest reliability  
Intraclass correlation coefficient in clinically 
stable children  
ICC = 0.52 (0.4-0.75 = fair/good).31,32 
Construct validity (evidence that 
the scale measures the construct 
it intends to)  
Association of PRSS with:  
1. Radiographic diagnosis (p<.05*) 
2. Functional status Questionnaire33 (r=0.6*) 
3. Parental/legal guardian overall 
assessment (r=0.4*) 
4. Physician assessment of severity (r=0.4*)  
 
1. p=.0003 (strong association) 
2. r = 0.53, p<.05 (c/w predicted) 
3. r = 0.38, p<.05 (c/w predicted) 
4. r = 0.28, p<.05 (c/w predicted) 
Responsiveness (an index of 
how well scale measures change) 
Standardized response mean 
SRM = 2.07 (>0.7 = excellent 
responsiveness)28,34,35   
Minimally important difference  
(the smallest degree of change 
that is clinically meaningful) 
MID calculated using distribution-based 
methods (i.e., using Standard Error of 
Measurement and half SD).30,35-40 
MID = 20% (i.e., a decrease of 20% 
from baseline = improvement) 
*Results predicted a priori 
 
Modification of the PRSS – During the analysis of the data from the PRSS validation study, we 
realized that expanding the number of response options would likely improve the psychometric 
properties of the scale. In particular, we were concerned about the possibility of a ceiling effect; 
patients with entering “a lot” of a certain symptom (the most severe response option available) 
would not be able to use the scale to indicate worsening. Accordingly we modified the PRSS by 

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increasing the number of response options from 3 to 6 (from “None”, “A Little”, “A lot” to “None”, 
“Almost None”, “A little”, “Some”, “A lot”, and “An Extreme Amount”) and administered it as an 
electronic diary to 65 children with acute sinusitis diagnosed at the Primary Care Center in 
Pittsburgh during the 2014-2015 respiratory season. Before administering the scale, however, 
we performed in-depth cognitive interviews with 75 patients regarding the wording of the 
individual questions, the new response options, the instructions, and modified the wording of 
some of the questions on the PRSS (see Supplement B below). The psychometric properties of 
the modified version of the PRSS (version 2.0) improved significantly. Specifically, (1) the 
proportion of child at the ceiling value was reduced by half for most items (e.g., 64% vs. 35% at 
ceiling for night time cough), (2) the responsiveness of the scale improved from 2.07 to 2.48, 
and (3) the test-reliability of the scale improved from 0.52 to 0.82. The MID of the scale 
remained stable at 20%. The modification of the scale does not change the sample size 
estimates; the new version has finer ratings for each of the eight items comprising the score 
(total maximum score increased from 16 to 40). Assuming these two discrete scales divide the 
underlying continuous scale into equal intervals, the standard deviation and the mean on the 
new scale should differ from those on the old scale by a factor of 2.5, which in fact they do (the 
baseline score and the average standard deviation across treatment and time both increased by 
2.5). Because the new version of the scale appears to result in primary summary statistics that 
are a multiple of those resulting from the old scale, and the tests being used are scale invariant, 
the original sample size estimates can be used. 
 
Identification of important prognostic factors 
We compared median time to resolution of symptoms (defined as reaching a score of ≤ 2 on the 
PRSS on two successive occasions) according to the levels of the potential prognostic factors 
(variables measured at baseline) using a proportional-hazards model in children receiving 
antimicrobial therapy for acute sinusitis. The only variable that remained independently 
associated with time to resolution after adjustment for baseline severity of symptoms was 
nasopharyngeal colonization with pathogens (S. pneumoniae, H. influenzae, M. catarrhalis) at 
baseline. Median time to symptom resolution in those with and without nasopharyngeal 
colonization with pathogens was 7.5 and 8.5 days, respectively (p=.008). In contrast, in two 
previous studies of children with URI who were not receiving antimicrobial therapy, the presence 
of pathogens predicted slower resolution of symptoms.27 Together, these findings suggest that 
in this trial, children who are colonized with pathogens will respond differently to treatment than 
those who are not colonized with pathogens (i.e., heterogeneity of treatment effect). Our 
preliminary data, which are similar to the data from Kaiser,19,20 suggest that testing for bacteria 
in the nasopharynx may assist greatly in identifying children who will respond to treatment with 
antibiotics. If we find that only those children colonized with pathogens benefit from antimicrobial 
therapy, then the management of children with suspected sinusitis could be similar to the 
management of children with streptococcal pharyngitis. A rapid antigen test for S. pneumoniae 
is commercially available, can be performed at the bedside, and has good accuracy (sensitivity 
88 to 92%, specificity 95 to 97%).41,42 Similar PCR-based tests for H. influenzae and M. 
catarrhalis have also been developed. By prescribing antimicrobials only to those with 
pathogens, antimicrobial prescribing could be sharply reduced. Of note, in our preliminary 
dataset, results were driven largely by the subgroup of children colonized with S. pneumoniae.27 
We suspect that this was due to the smaller number of children colonized with H. influenzae and 
M. catarrhalis. The ability of the PRSS scale to discern differences in time to resolution 
according to the presence or absence of pathogens in the nasopharynx further supporting its 
utility and validity. In summary, our preliminary study supports using the presence of pathogens 

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in the nasopharynx to define subgroups and using the PRSS scale as the primary outcome 
measure. 
           
Identification of important diagnostic factors 
Relatively little data exist regarding the accuracy of individual signs and symptoms of sinusitis in 
children. Accordingly, one of the goals of our preliminary study was to identify signs and 
symptoms that could discriminate children with true bacterial sinusitis from children with an 
uncomplicated URI. However, because no practical gold standard exists for the diagnosis of 
bacterial sinusitis, we proposed to use radiography and nasopharyngeal culture results as 
reference standards. We reasoned that it would be very unlikely for children with no pathogens 
in their nasopharynx to have bacterial sinusitis. Similarly, although radiographs have are 
frequently positive in children with URI, normal radiographs are very unlikely in children with 
significant sinusitis.43 Thus, we reasoned that use of both tests together could be used to divide 
children into two groups: those with “likely URI” (negative NP swabs OR negative X-rays) vs. 
those with “possible bacterial sinusitis” (positive NP swabs AND positive X-rays). This approach 
is admittedly less accurate than sinus aspiration; some children with a positive swab and a 
positive X-ray will have viral URI (because the positive predictive value of these findings is low). 
Nevertheless, because our goal is restricting antibiotic use, not perfect prediction, using these 2 
tests could serve as a reasonable “silver standard” against which the accuracy of signs and 
symptoms commonly attributed to sinusitis could be assessed. Although all children enrolled in 
our preliminary study met the diagnostic criteria set forth in the American Academy of Pediatrics 
(AAP) guidelines, only 79/204 (39%) were classified as having “possible bacterial sinusitis”. Of 
the signs and symptoms investigated, colored nasal discharge, was the only finding associated 
with “possible bacterial sinusitis”. Colored discharge was independently associated with the 
presence of NP pathogens (p<.003) and with abnormal sinus radiographs (p<.001) even after 
controlling for other variables (e.g., age). Thus, our results support using colored discharge to 
define the subgroups in this trial. 
 
Survey of current practice supports equipoise. Genuine uncertainty exists among 
practicing clinicians regarding the need for routine antimicrobial treatment of children with acute 
sinusitis. In a survey of 68 community pediatricians affiliated with Children’s Hospital of Pittsburgh 
of UPMC (response rate 86%), only 56% and 32%, respectively, reported routinely prescribing 
antibiotics for children meeting criteria for persistent and worsening presentations of acute 
sinusitis. The AAP sinusitis guideline committee was divided between those who favored 
immediate antimicrobial treatment and those who favored initial observation for children with 
persistent symptoms. Thus, in recognition of the substantial rate of spontaneous resolution among 
children diagnosed as having acute sinusitis,6 the guideline1 includes an option for initial 
observation for children with persistent symptoms (who constitute at least 85% of all children 
diagnosed with acute sinusitis).2 Given the current uncertainty among practicing pediatricians and 
the observation-only option offered by the guideline, a placebo-controlled trial is appropriate and 
warranted. 
 

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2.2 
Scientific Rationale 
2.2.1 Rationale for the trial 
2.2.1.1 
Inadequate data on efficacy of antibiotics 
Despite the large numbers of children who are treated with antibiotics for acute sinusitis, 
surprisingly little evidence exists to support antibiotic treatment. Only 3 placebo-controlled, 
randomized clinical trials have assessed the benefit of antimicrobial therapy for acute sinusitis 
(Table 2). A fourth study was excluded from the discussion below because no minimum duration 
of symptoms was required for inclusion;5 thus, the majority of children included had what would 
be today classified as uncomplicated viral upper respiratory tract infections (URIs). The 
numbers of children enrolled in these trials were relatively small (111 children received placebo 
in the three trials combined),2,6,7 and the inclusion criteria differed from trial to trial, and from 
diagnostic criteria for sinusitis set forth in current guidelines. The earliest trial7 used signs and 
symptoms of sinusitis plus abnormal imaging of the sinuses to select children for enrollment, 
thus its results are not directly applicable. The results of the two more recent trials2,6 were 
contradictory: the smaller trial supported antimicrobial treatment whereas the larger trial 
supported observation only. It seems questionable to recommend antimicrobial treatment based 
on the results of a trial in which only 28 children received placebo in light of a previous study 
twice as large that had contrary results. Similarly, it seems questionable to routinely recommend 
observation when clear evidence exists that some children improve more rapidly with antibiotics 
than without. Accordingly, the 3 randomized controlled trials conducted to date do not allow 
meaningful conclusions to be reached about the efficacy of antimicrobials. This is reflected in 
the contradictory recommendations proposed by different guideline committees.1,8-10 A critical 
need exists for a placebo-controlled trial large enough to determine not only whether 
antimicrobial therapy is beneficial overall, but also whether there are definable subgroups of 
children for whom antibiotics are, or are not, sufficiently beneficial to justify their use. By 
addressing some of the limitations of previous trials, this study will provide data regarding the 
efficacy of antimicrobial therapy in children with acute sinusitis. 
 
 Table 2. Summary of Randomized Controlled Trials to Date and of the Current Trial 
 
Wald et al., 19867 
Garbutt et al., 20016 
Wald et al., 20092 
Current trial 
N 
93 (35 on placebo) 
188 (55 on placebo) 
58 (28 on placebo) 
688 (344 on placebo) 
Age 
2-16 years 
1-18 years 
1-10 years  
2-12 years 
Inclusion 
criteria 
Persistent symptoms 
and positive X-ray 
Persistent symptoms 
Persistent, worsening, or 
severe symptoms  
Persistent or worsening 
symptoms 
Treatment 
arms 
Amox, Amox-clav, 
placebo 
Amox, Amox-clav, 
placebo 
Amox-clav, placebo 
Amox-clav, placebo 
Primary 
Outcome  
Fewer than 2 
symptoms present on 
Day 10 on a 10-item 
questionnaire (not 
validated) 
Change in score from 
baseline to Day 14 on a 
5-item scale with 
questionable validity 
Fewer than 2 symptoms 
present on Day 14 on a 
10-item questionnaire (not 
validated) 
Symptom score over the 
first 10 days using a 
validated scale (i.e., 
repeated measures over 
time)  
Result 
66% vs. 43% cure with 
antibiotics vs. placebo 
No difference on Day 
14 
50% vs. 14% cure with 
Amox-clav vs. placebo  
To be determined 
Major 
limitations 
• 1˚ outcome 
dichotomous 
• 1˚ outcome assed on 
one particular day 
• Change in score not 
ideal for measures 
with high variability 
• 1˚ outcome dichotomous 
• 1˚ outcome assed on 
one particular day 
• 1˚ outcome will 
measure symptom 
burden over time 

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• Excluded children 
with normal 
radiographs or with 
history of asthma  
• Analysis not per 
intention-to-treat 
principle 
• Dose of amoxicillin 
likely not effective for 
children with resistant 
S. pneumoniae 
• Not powered to detect 
whether treatment effect 
differed in children with 
the 3 included 
presentations  
• Fewer children enrolled 
than expected 
• Adequate doses of an 
effective antibiotic will 
be used 
• Analysis per intention-
to-treat principle 
• Power calculation 
based on reliable 
preliminary data 
 
2.2.1.2 
Deficient methods used in previous trials 
1) None of the previous trials tracked symptoms on a daily basis. Instead symptoms were 
assessed by telephone interview at fixed time points. Comparing symptoms on any given 
day is likely to be less sensitive than comparison of the burden of disease over time. 
2) The primary outcome in all 3 studies to date was assessed on day 10 or 14. Because 
symptoms of sinusitis resolve spontaneously over time, comparison of symptoms this late in 
the course of disease is not ideal. 
3) None of the previous trials used a properly validated symptom severity scale to measure 
response to therapy. The scale developed by Garbutt et al.11 was psychometrically 
evaluated, but its construct validity appears questionable because no data were reported 
regarding the scale’s correlation with other measures of functional status or with measures 
of sinusitis severity. Furthermore, parents/legal guardians/children did not provide any input 
regarding the importance of the items included in the scale. The questionnaire developed by 
Wald et al.2 was not psychometrically evaluated. 
 
2.2.1.3 
Current diagnostic criteria lack specificity for bacterial disease 
The current conventional approach in the US is to diagnose acute sinusitis in children with a 
URI whose clinical course is atypical, characterized by prolonged and/or worsening symptoms. 
Although this approach has had some success in reducing the number of children treated 
inappropriately with antibiotics, it needs to be refined for several reasons. First, because 
persistent or worsening upper respiratory symptoms may be due to causes other than bacterial 
superinfection (e.g., closely spaced sequential viral infections, asthma, allergic rhinitis). And 
second, because some uncomplicated viral infections may nonetheless be persistent or 
biphasic. A recent meta-analysis of studies of children with URI reported that 50% of children 
were still symptomatic at 10 days.12 Although the majority of uncomplicated viral URIs are 
improving by 10 days, many children will continue to have residual respiratory symptoms which 
may be over interpreted by their parents/legal guardians or physicians. All of these factors may 
lead to the over diagnosis of sinusitis and to the prescription of unnecessary antibiotics. 
Accordingly, it is likely that many children diagnosed with acute sinusitis using the current 
criteria actually derive no benefit from antimicrobial therapy. 
 
2.2.1.4 
This trial may allow us to make diagnostic criteria more specific for 
bacterial disease. 
Development of accurate diagnostic criteria would ideally require a cohort of children with 
clinically suspected sinusitis to undergo aspiration of the maxillary antrum. Signs and symptoms 
associated with the recovery of bacteria from the sinus could then be used to accurately identify 
those with bacterial disease. Unfortunately, sinus aspiration is invasive, often requires sedation, 
is technically difficult, and is recommended only for children who have severe disease, are 

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immunocompromised, or have infections that are unresponsive to antibiotic treatment. 
Accordingly, by necessity, the current diagnostic criteria were developed on the basis of clinical 
observations of the course of typical viral URIs, with acute sinusitis assumed when the duration 
or quality of children’s symptoms differed significantly from the typical presentation. To our 
knowledge, no other infectious disease for which antibiotics are so frequently prescribed is 
diagnosed based simply on the duration or course of symptoms; diagnosis usually rests upon 
reliable findings on examination (as in acute otitis media) or direct testing for presence of 
bacteria (as in streptococcal pharyngitis). Because of the inaccuracies inherent in the current 
criteria, refinements are needed that would make the criteria more specific for bacterial disease. 
Instead of using sinus aspiration or imaging, we will use differential response to antibiotic 
therapy as a means of identifying children with bacterial disease. In other words, examination 
of response to treatment in various subgroups (defined a priori) in this large randomized, 
placebo-controlled trial represents a unique and innovative approach to refining the 
diagnostic criteria for acute bacterial sinusitis in children. 
 
2.2.2 Rationale for using NP colonization to identify the subgroups 
2.2.2.1 
Bacterial superinfection more likely when pathogens present 
Like Acute Otitis Media (AOM), acute bacterial sinusitis is a superinfection that originates from 
bacteria in the nasopharynx. The negative predictive value of a nasopharyngeal culture for 
isolating the same organism from the middle ear is consistently >90%.14-18 Thus, when 
pathogens are absent from the nasopharynx, bacterial superinfection of the middle ear is highly 
unlikely. No similar recent studies exist for acute sinusitis, presumably because sinus aspiration 
is considerably more invasive. Nevertheless, sinusitis and otitis are similar conditions. It seems 
reasonable to suppose that acute bacterial sinusitis will also be highly unlikely when no 
pathogens are present in the nasopharynx. Even if the negative predictive value of the NP 
culture is in the 75-90% range, it may nonetheless prove useful in practice because unlike AOM, 
where the diagnosis can be readily and accurately accomplished through direct–i.e. otoscopic–
examination, the diagnosis of sinusitis cannot. 
 
2.2.2.2 
Children with pathogens in NP benefit more from antimicrobials 
In two trials comparing antibiotics to placebo, Kaiser compared the resolution of symptoms in 
adults with URI or sinusitis according to the presence of pathogens in the nasopharynx.19,20 In 
patients with no pathogen recovered from the nasopharynx, there was no difference between 
treatment arms in terms of symptom resolution (i.e., no benefit of therapy). In contrast, in those 
with pathogens recovered from their nasopharynx, symptoms resolved significantly more rapidly 
in the antibiotic arm. This study in adults suggests that the presence of pathogens in the 
nasopharynx holds promise also as a method of selecting children who are likely to benefit from 
antimicrobial therapy. 
 
 
2.2.3 Rationale for using colored nasal discharge to define subgroups 
In both children and adults, the presence of colored nasal discharge has been associated with 
the presence of S. pneumoniae, H. influenzae, and M. catarrhalis in the nasopharynx.20,21 In a 
preliminary study, we found a robust association between the presence of nasopharyngeal 
pathogens and the presence of colored (green/yellow) nasal discharge (P<.003, see below). 

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Colored nasal discharge has been associated with response to antibiotics in adults with 
sinusitis; a recent individual patient data meta-analysis compared the number to the needed to 
treat (NNT) in the subgroup of adults with visible purulent discharge in the pharynx with the NNT 
for the overall group with acute rhinosinusitis. Compared to the overall group, those with visible 
discharge were more likely to benefit from antimicrobial therapy (NNT 8 and 15, respectively).22 
European and Canadian sinusitis guidelines use purulent nasal discharge to select children for 
antimicrobial treatment.8,23 Most (86%) pediatricians in the US consider the presence of colored 
nasal discharge as “very important” or “moderately important” in their decision to diagnose acute 
sinusitis, and second in importance only to duration of symptoms.24 Thus, it appears necessary 
to establish whether or not this finding is useful in selecting children who may benefit from 
antimicrobial therapy. Assessing for colored nasal discharge as a proxy for bacterial disease is 
appealing because it does not require microbiologic testing. 
2.2.4 Rationale for placebo  
A placebo arm is necessary to identify subgroups of children who do not require treatment. This 
will also help establish the natural history of the disease. A comparative trial comparing one 
antibiotic with another or a short vs. long course of an antibiotic would be premature at this time. 
 
2.2.5 Rationale for the use of clavulanate 
In our preliminary data, 48% of H. influenzae isolates and 100% of M. catarrhalis isolates 
produced ß-lactamase. Furthermore, the incidence of disease caused by H. influenzae may be 
increasing secondary to routine vaccination with pneumococcal conjugate vaccine.14,44 Thus, 
the use of amoxicillin-clavulanate potassium instead of amoxicillin alone seems prudent. The 
most recent guideline from the Infectious Diseases Society of America (IDSA) recommends 
amoxicillin-clavulanate potassium as the preferred agent for sinusitis in children.45 The AAP 
guideline recommends using amoxicillin with or without clavulanate potassium as the first-line 
agent.1 
 
2.2.6 Rationale for using the high-dose amoxicillin-clavulanate 
potassium 
In our preliminary study, 23% of the S. pneumoniae isolates were penicillin-nonsusceptible. In 
addition, 6% of the non ß-lactamase producing H. influenzae isolates were ampicillin-
nonsusceptible. A higher dose of amoxicillin would be needed to treat these ampicillin/penicillin-
resistant isolates of S. pneumoniae and H. influenzae. Furthermore, data collected after 
widespread use of Pneumococcal Conjugate 13-valent vaccine (PCV-13) indicate46 that many of 
the emerging serotypes appear to be resistant to penicillin. The rates of diarrhea are no higher 
when using the high-dose formulation of amoxicillin-clavulanate (because it contains relatively 
less clavulanate).47,48 
 

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2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
1)   Amoxicillin clavulanate potassium - The most common side effect of amoxicillin 
clavulanate is diarrhea. Diarrhea is reported by about one third to one half of children who 
take this medication. Infrequently, children may develop vomiting, nausea, diaper rash, or 
abdominal pain. Rarely, anaphylaxis (a severe allergic reaction) may occur. The use of 
antibiotics has been linked to the development of resistant bacteria, both in the child 
receiving antibiotics and in the community at large. Finally, there is a risk that the child will 
not respond to amoxicillin clavulanate, and thus require a different treatment. Most of the 
reported side effects of amoxicillin clavulanate are mild to moderate and resolve when the 
medication is stopped. 
 
 
2)   Placebo - There is a theoretical risk that children receiving placebo may be symptomatic 
for a longer period of time or have more complications than children receiving antibiotics. 
None of the studies to date, however, have borne this out. The largest study to date found 
no difference in the time-to-resolution of symptoms in children on antibiotics. Similarly, 
there is no evidence that immediate treatment with antibiotics is more effective at 
preventing complications of sinusitis. Most complications of sinusitis seem to occur in older 
children (who are not included in this study) and occur during the first few days of an upper 
respiratory tract infection (before sinusitis is usually diagnosed). Placebo contains no 
active medications and an allergic reaction is very rare. 
 
3)   Nasopharyngeal swab - The NP swab may cause minor transient discomfort. 
 
4)   Loss of confidentiality - There is a rare risk of breach of confidentiality. Subjects will be 
asked to provide personal health information (PHI).  All attempts will be made to keep this 
PHI confidential within the limits of the law.  However, there is a chance that unauthorized 
persons will see the subjects’ PHI.  All records will be kept in a locked file cabinet or 
maintained in a locked room at the participating clinical study sites.  Electronic files will be 
password protected.  Only people who are involved in the conduct, oversight, monitoring, 
or auditing of this study will be allowed access to the PHI that is collected.  Any 
publications from this study will not use information that will identify subjects by name.  
Organizations that may inspect and/or copy research records maintained at the 
participating clinical study sites for quality assurance and data analysis include groups, 
such as the National Institute of Allergy and Infectious Diseases (NIAID) and Food and 
Drug Administration (FDA). A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by US Law.  This web site will not include 
information that can identify subjects.  At most, this web site will include a summary of the 
results. 
 
5) Internet Communication/Text Messaging- Although every reasonable effort has been 
taken, confidentiality during Internet communication activities cannot be guaranteed and it 
is possible that additional information beyond that collected for research purposes may be 
captured and used by others not associated with this study. Text message are not 

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encrypted or secure during their transmission. Text messages could be intercepted and 
used by others not associated with this study.  
 
6) Mid-Turbinate Nasal Swab. The mid-turbinate (MT) nasal swab may cause some 
discomfort. 
 
 
The risk to children receiving placebo will be negligible for several reasons. First, in the context 
of this trial, placebo is not equivalent to “no treatment”. We will be monitoring changes in the 
PRSS score on a daily basis and those whose scores are worsening or not improving as 
expected will be evaluated without delay and treated with rescue antibiotics, as clinically 
indicated. Parents/legal guardians without reliable phone service will not be enrolled. In addition, 
parents/legal guardians will have 24-hour access to the study physicians who will arrange a 
study visit, usually within 24 hours, if indicated. Close follow-up and early treatment of children 
who appear to be worsening–the strategy proposed here–may be equally or more effective at 
preventing suppurative complications than routine prescription of antibiotics with no planned 
active follow-up, which is the standard of care. As such, our study will be similar to a study 
comparing immediate antimicrobial treatment with delayed prescription, the only difference 
being that parents/legal guardians and children can be more easily blinded using the design 
proposed here. We have an excellent track record of ensuring the safety of children in placebo-
controlled trials. We recently completed a placebo-controlled trial in which we followed 147 
children under 2 years of age with AOM who had been randomized to receive placebo.49 
Children in this study will be relatively less vulnerable because they will be older and many will 
be verbal. Second, we are excluding children at risk for complications of sinusitis (i.e., those 
with a severe presentation, systemic toxicity, immunodeficiency, and comorbid conditions). Most 
children enrolled will be well-appearing. In our preliminary dataset, only 3% of children had a 
temperature ≥38˚C at presentation. Third, suppurative complications of acute sinusitis are 
rare,50 occur most often in adolescents51 (whom we are excluding), and often occur 
unexpectedly within the first few days of the onset of URI symptoms,52 well before the diagnosis 
of sinusitis would likely have been made. The routine use of pneumococcal conjugate vaccine is 
likely to further reduce the incidence of complications. Finally, although the rationale for 
antimicrobial therapy is faster resolution of symptoms, we do not believe that children receiving 
placebo will experience disproportionate suffering; no differences in time-to-resolution of 
symptoms was found in studies to date.6 On the other hand, the potential harms associated with 
antimicrobial therapy (diarrhea, diaper dermatitis, risk of hypersensitivity reaction, potential to 
induce resistance) are well-documented and quite prevalent. Including children with “worsening” 
symptoms poses no undue risk to their safety; in our preliminary study, these children were no 
more likely than children with persistent symptoms to have either nasopharyngeal colonization 
with respiratory pathogens (45% vs 48%, p=0.85) or positive radiographs (p=78% vs 80%, 
p=0.75). Further, only 32% of pediatricians surveyed treat children with this presentation 
routinely. Accordingly, for children with the “worsening” presentation, the risks of withholding 
antibiotics, if any, would be lower in this trial than in usual practice. 
 
There may be other unknown risks, discomforts, or side effects. 
2.3.2 Known Potential Benefits 
 

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Children receiving placebo may benefit from participation in this trial because they will not be 
exposed to the side effects of antimicrobial therapy (diarrhea, diaper rash, development of 
resistant bacteria, anaphylaxis). This trial will also generate generalizable knowledge about the 
treatment of acute sinusitis in children. 

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3 
OBJECTIVES 
3.1 
Study Objectives 
 
Primary 
• 
To determine whether the effect of antimicrobial treatment differs in predefined 
subgroups of children with acute sinusitis (i.e., to test for treatment subgroup 
interactions). Subgroups will be defined by the (1) presence vs. absence of 
nasopharyngeal (NP) colonization with respiratory pathogens (Streptococcus 
pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis), and (2) presence vs. 
absence of colored (yellow or green) nasal discharge. 
Secondary 
• 
To determine whether antimicrobial therapy is superior to placebo (i.e., to test for the 
overall effect)  
Tertiary 
• 
To evaluate compliance with study product 
• 
To assess adverse events associated with use of amoxicillin clavulanate, including the 
development of bacterial resistance 
• 
To compare resource utilization according to treatment strategy 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
 
The PRSS scale (Supplement B) will be completed on a daily basis (in the evenings) from the day 
of enrollment (Day 1) to Day 11. PRSS scores over the first 10 days of therapy will be the primary 
outcome variable (i.e., repeated measures over time will be used to measure disease burden). 
3.2.2 Secondary Outcome Measures 
 
Secondary Efficacy Outcomes 
 
1) Treatment failure – Children who are not improving at the expected rate will be identified 
through daily monitoring of PRSS scores. These children will be seen by the study team and 
rescue medication will be prescribed as clinically indicated. We will define treatment failure 
as follows: 
a. Worsening at any time–PRSS score increased by >20% from entry. 
b. No change by 48 hours–PRSS score decreased by <2 points from entry (Day 1) to 
Day 3. 
c. Failure to improve significantly by 72 hours–PRSS score decreased by <20% from 
entry (Day 1) to Day 4. 
d. PRSS decreased by <20% from enrollment on 2 consecutive occasions Days 5-11 
e. Still symptomatic (PRSS score ≥50% of entry score) at the time of the end-of-study 
follow-up visit (Days 12 to 18). 
 

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This definition is similar to that used by clinicians in practice. A similar composite outcome 
was used successfully in previous studies by Dr. Wald.2,7 Days 3 and 4 were chosen as 
decision points because most (>90%) treatment failures are expected to occur around that 
time.2 A 20% change was chosen because this represents the smallest change that appears 
to be clinically meaningful (see Table 1). Using these definitions, we estimate, based on our 
preliminary data and on the failure rates observed in previous studies using the same 
antibiotic,2,7,49,53 that the rate of treatment failure in the antibiotic arm will be approximately 
15%. 
2) Development of AOM (acute symptoms and a bulging tympanic membrane) on Days 1 to 
11. 
3) Receipt of an antibiotic (other than the assigned study medication) on Days 1 to 11 for any 
indication. 
3.2.3 Tertiary outcomes 
 
Safety Outcomes 
1) Adverse events - The proportions of children experiencing adverse events will be compared. 
We will also track the duration of each reported adverse event. This will include a 
comparison of the number of children at the follow-up visit who have resistance organisms. 
Diarrhea will be defined as the occurrence of ≥3 watery stools in 1 day or 2 watery stools per 
day for 2 consecutive days, and will be tracked in the daily diary. 
2) Compliance - In the daily diary, we will ask parents/legal guardians to record whether they 
administered the doses of study product. Administration of ≥70% of the doses will be 
considered compliant. 
 
Other outcomes 
1) Resource utilization 
a. Direct medical costs (costs of visits to healthcare providers plus cost of medications). At 
the end-of-study follow-up visit, we will ask parents/legal guardians about the number 
and type of encounters with healthcare providers since enrollment. Similarly the number 
and types of medication used will be ascertained. 
b. Indirect costs: At the end-of-study follow-up visit, information will be collected on the 
indirect costs associated with the diagnosis of acute sinusitis, including travel expenses, 
alternate child care expenses for the patient and/or siblings, as well as time costs (e.g., 
for missed work). 
 

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4 
STUDY DESIGN 
This is a large, multi-center, randomized, double-blind, placebo-controlled, parallel group trial 
comparing antimicrobial treatment with amoxicillin-clavulanate potassium with matching placebo 
in children aged 2 years through 12 years of age, who meet the current AAP criteria for sinusitis. 
(See Schematic of Study Design). 
 
Participants will be recruited from the primary care clinics at 5 sites: (1) Children’s Hospital of 
Pittsburgh of UPMC and its affiliated Pediatric PittNet Practice Based Research Network 
(PBRN), CCP South Hills Pediatric Associates and CCP HealthQuest Hampton, Pittsburgh (Site 
PI and study Co-PI: Nader Shaikh); (2) Kentucky Pediatric and Adult Research, Bardstown, KY 
(Site PI: Stanley Block); (3) University of Wisconsin, Madison, WI (Site PI and Study Co-PI: 
Ellen Wald) and (4) Cyn3rgy Research (Site PI: Frank Calcagno). 
 
Children will be randomized 1:1 to receive treatment for 10 days with either twice daily 
amoxicillin-clavulanate or matching placebo. Randomization will occur in blocks of 4 and study 
participants and study personnel (except the research pharmacist) will be masked to treatment 
allocation. Stratification will be based on the presence/absence of colored (yellow or green) 
nasal discharge and site of enrollment. Randomization codes will not be broken until completion 
of the trial unless there is a medical emergency that necessitates unmasking. A total of 688 
children (approximately 344 in each treatment group), who meet the current AAP criteria for 
sinusitis will be enrolled over a 5-year period. Each participant will be followed for 12 to 18 days. 
Antimicrobial therapy will consist of amoxicillin-clavulanate suspension, 90 mg/kg/day divided 
into two equal doses. The placebo will be nearly identical in color, taste, and consistency to 
amoxicillin clavulanate. Amoxicillin clavulanate suspension will be purchased (Augmentin® 
Pediatric Suspension from Teva Pharmaceutical Industries Ltd.) and rebottled by the University 
of Pittsburgh Medical Center Investigational Drug Service (IDS). Both Amoxicillin clavulanate 
and placebo will be similarly labeled with a code number that masks site investigators, site staff, 
parents/legal guardians and children to the formulation. Study medication will be distributed to 
clinical sites by the IDS. 
 
Treatment effect will be measured primarily using the validated Pediatric Rhinosinusitis 
Symptom Scale (PRSS) which will be administered every evening as an electronic diary. Once 
a day, we will send parents/legal guardians a text message and/or an email with a link to a 
secure website where they will be able to complete the PRSS. Versions for both a personal 
computer and a smart phone will be available. We will ensure that parents/legal guardians 
understand the process of completing the diary by having them complete a mock entry either on 
their personal cell phones or on the research personal computer (PC) or tablet at the enrollment 
visit. We will reimburse parents/legal guardians $5 for every diary entry completed on the day 
the alert was sent. Parents/guardians, who complete all diary entries, will be reimbursed an 
additional $30. Parents/legal guardians who do not have access to the internet will be loaned a 
tablet (with limited functionality) which they can use to complete the entries. We will design the 
electronic diary so as to prohibit incomplete forms from being submitted. If the parent/legal 
guardian does not complete the diary for a given day, we will call or text them the next morning 
to collect this information and to encourage them to complete the diaries for the following days. 
 
Every morning (including weekends), we will call or text parents/legal guardians whose evening 
PRSS score is missing. If the PRSS score is missing, this information will be collected over the 

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phone. If a child’s PRSS score is not improving as expected, an interim evaluation will be 
scheduled, usually on the same day. A study team member will be available 24 hours/day, 7 
days/week via cellular phone. Children failing study product will be treated with clindamycin plus 
cefixime, amoxicillin-clavulanate potassium, or levofloxacin, or a similar antibiotic, as clinically 
indicated and without breaking the blind. The results of the nasopharyngeal (NP) culture (growth 
of S. pneumoniae, H. influenzae, and/or M. catarhallis) may be used to guide therapy. Although 
growth of Group A. Streptococcus will be ascertained, this will not be used for patient 
management (because the absence of pharyngitis on exam indicates that the patient is a carrier, 
which does not require intervention). 
 
An end-of-study follow-up clinic visit will be held once during Days 12 to 18. If the parent/legal 
guardian is unable or unwilling to return for the end-of-study follow-up visit, we will offer to visit 
the patient’s home. 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
Subject Inclusion Criteria 
 
Children 2 to 12 years of age with persistent and worsening presentations of acute bacterial 
sinusitis, as defined in the latest AAP guideline,1 will be included. Persistent symptoms will be 
defined as 11 to 30 days of nasal symptoms and/or cough (not exclusively nocturnal), that is not 
improving. Worsening symptoms will be defined as worsening nasal symptoms or worsening 
daytime cough or a  
new fever in children 
who were apparently 
recovering from a 
viral URI. These two 
presentations 
constitute a large 
majority of children 
with sinusitis 
(>95%).2 Because 
resolution of 
symptoms (as 
measured by the 
PRSS) is our primary 
outcome, a score of 
≥9 on the PRSS will 
be required. 
5.2 
Subject Exclusion Criteria 
We will exclude children with a history of asthma who are actively wheezing or who have cough 
as the sole presenting symptom, and children with a history of allergic rhinitis whose respiratory 
symptoms have not acutely worsened. Other exclusion criteria are summarized in the Table 3. 
5.3 
Treatment Assignment Procedures 
 
Children will be randomized centrally in a 1:1 ratio to receive either oral amoxicillin-clavulanate 
or placebo, each administered twice daily for 10 days. Ten days was chosen because this is the 
duration most frequently used in practice.24 
5.3.1 Randomization Procedures 
Randomization will occur in blocks of 4 and investigators and participants will be masked to 
treatment allocation. Stratification will be based on the presence/absence of colored (yellow or 
green) nasal discharge and site of enrollment. 
 
High-dose amoxicillin-clavulanate potassium (90/6.4 mg/kg/day, maximal dose: 4 g/day, Teva 
Pharmaceutical Industries LTD., see Other Attachments section for product insert) or placebo 
Table 3. Eligibility Criteria 
Inclusion Criteria 
Exclusion Criteria 
• 2 -12 years of age (before 12th 
birthday) 
• Persistent sinusitis: URI 
symptoms present for >10 days 
without improvement (11-30 days) 
• Worsening sinusitis: URI 
symptoms worsening after a 
period of improvement (6-10 
days) 
• PRSS score ≥9  
• ≥2 doses of pneumococcal 
conjugate vaccine or appropriate 
for age. 
• Sinusitis with severe presentation (≥3 days of 
colored nasal discharge and fever  ≥ 39˚ C)  
• Immotile cilia syndrome, cystic fibrosis, 
immunodeficiency 
• Parental/legal guardian inability to read/write 
English or Spanish 
• Allergy to Amoxicillin-clavulanate 
• Other concurrent infection (e.g., pneumonia, 
acute otitis media, streptococcal pharyngitis) 
• Asthma/allergic rhinitis explains symptoms 
• Not reachable by phone 
• Systemic toxicity  
• Wheezing on exam 
• Systemic antibiotic use within 15 days 
• Prior Sinus surgery 
 

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will be administered twice daily for 10 days. Placebo for all study sites will be prepared centrally 
by a research pharmacist at the University of Pittsburgh Medical Center Investigational Drug 
Service (IDS). The IDS is well suited to this task because it is currently preparing the same 
placebo (for amoxicillin-clavulanate) for our multicenter NIAID-sponsored AOM study (BAA-
NIAID-DMID-NIHAI2009058). All study medications will be packaged in containers of identical 
appearance and will be labeled with a unique number. The IDS will maintain drug accountability 
records for all participating sites. 
Per International Council for Harmonization (ICH) guidelines, screening records will be kept at 
each participating clinical study site to document the reason why an individual was screened but 
failed trial entry criteria. 
All study personnel except the research pharmacist at the UPMC Investigational Drug Service 
will be masked to treatment group assignment. The subjects and parents/legal guardians of 
study subjects will also be masked to treatment group assignment. Randomization codes will 
not be broken until completion of the trial. Only in the event of a medical emergency and if 
unmasking would change the selection of treatment, will subject treatment assignment be 
revealed. The ISM or PI may unmask the treatment for a subject by contacting the Research 
Pharmacist at the UPMC Investigational Drug Service. Unmasked subjects will complete any 
remaining protocol assessments (diaries and routine end-of-study follow-up visit). When 
considering unmasking treatment for a subject, the investigator should consider whether 
knowing the identity of the treatment would change the selection of treatment. If knowledge of 
the subjects’ treatment assignment would not affect treatment decisions, unmasking will not 
occur. 
5.3.2 Reasons for Withdrawal 
The following events are to be considered sufficient reason for discontinuation of a subject from 
the study product: 
• 
Parents/legal guardians request; subjects are free to withdraw from participating in the 
study at any time upon request. 
• 
Parents/legal guardians who do fail to complete any of the diaries during the first 4 days 
of the study will be withdrawn for non-compliance. 
5.3.3 Handling of Withdrawals 
If a parent/legal guardian is unwilling to continue follow-up through scheduled study visits, the 
subject will be referred back to their primary care provider (PCP) for continued antibiotic 
treatment and follow-up. Subjects withdrawn due to non-compliance will be replaced.  
 

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5.3.4 Termination of Study 
The study will be completed when all enrolled subjects have completed follow-up or when the 
DSMB or DMID determines that the study needs to be terminated. 
 

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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
6.1.1 Acquisition 
The amoxicillin-clavulanate used in this study is amoxicillin-clavulanate potassium suspension, 
administered at a dosage of 90/6.4 mg/kg/day in 2 divided doses for 10 days, manufactured by 
Teva Pharmaceutical Industries Ltd. This drug is currently licensed for use in children with 
sinusitis (see Other Attachments section for product insert). It will be rebottled centrally at the 
IDS and reconstituted at each site. 
 
The placebo used in this study, administered in 2 divided doses for 10 days, will be developed 
by the IDS using a formula which has been extensively tested to ensure similarity of taste, 
thickness (texture), odor and appearance (color) with the active product. It will be prepared 
centrally at the IDS and will be reconstituted at each site. The IDS at the University of Pittsburgh 
is well suited to this task because it is currently preparing the same placebo (for 
amoxicillin/clavulanate) for our multicenter NIAID-sponsored AOM study (BAA-NIAID-DMID-
NIHAI2009058). 
6.1.2 Formulation, Packaging, and Labeling 
All study product (whether active treatment or placebo) will be presented in identical prescription 
bottles with safety caps. Further details regarding formulation, packaging and labeling are 
included in the protocol-specific Manual of Procedures. 
6.1.3 Product Storage and Stability 
The research pharmacist at IDS will ensure that all study product is stored in a secured (locked) 
area at a temperature of 15-30°C (monitored on a daily basis). At the participating clinical study 
sites, study product will be stored at this temperature in a dedicated locked storage area with 
logs to track temperature stability. The temperature will be recorded once daily when the study 
nurse is working. When the nurse is not working (weekends, holidays, vacation, sick days, etc.) 
the temperature will be recorded in a minimum/maximum style. In the event of documentation of 
ambient temperature outside the above range, study product will not be administered and the 
participating clinical study site investigator or coordinator will contact the sponsor and research 
pharmacist at the IDS for further instructions. No stability studies on the un-reconstituted active 
or placebo are necessary or will be conducted after transfer to the study bottles. The active 
product will not be changed in any way. Study product will be given a one-year expiration after 
transfer (or earlier if the product has an earlier expiration). 
6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
See the protocol-specific MOP for detailed information regarding the reconstitution of study 
product. 

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A designated study product administrator (SPA) at each of the participating clinical study sites 
will reconstitute the study product and provide parents/legal guardians with sufficient study 
product for 10 days. 
• 
Active Treatment Group: Parents/legal guardians will be provided with amoxicillin-
clavulanate potassium at 90/6.4 mg/kg/day in 2 divided doses for 10 days. 
• 
Placebo Group: Parents/legal guardians will be provided with placebo in 2 divided doses 
for 10 days. 
Parents/legal guardians will be instructed to record each dose of study product given to the 
subject in the daily electronic diary. Parents/legal guardians will be instructed on proper 
measurement and handling and storage of reconstituted study product. Suggested times for 
administration of study product will be 7:00 AM and 7:00 PM with a meal or a snack. Subjects 
enrolled prior to 1:00 PM will be given the first dose of study product at the time of enrollment 
and a second dose at 7:00 PM that day. Subjects enrolled in the afternoon (after 1:00 PM) will 
receive the first dose at the time of enrollment and the second dose the next morning. 
Subsequently, some children will receive the final dose of study production in the morning of 
Day 11. 
6.3 
Modification of Study Intervention/Investigational Product for a 
Participant 
Children failing study product and children in whom study product is discontinued because of 
adverse events will be treated with clindamycin plus cefixime, amoxicillin-clavulanate potassium, 
or levofloxacin, or a similar antibiotic, as clinically indicated and without breaking the blind. The 
results of the NP culture may be used to guide therapy. 
6.4 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
Study product will be supplied by the IDS to all participating clinical sites. The SPA at each site 
will inventory, record and acknowledge receipt of all shipments of the study product. All study 
product will be accounted for in the electronic case report form and study product accountability 
inventory forms. The randomization assignment system will be generated by the Data 
Management and Statistical Unit in the Division of General Academic Pediatrics at the 
Children’s Hospital of Pittsburgh. For each subject, the SPA will document the specific bottle 
number and volume of study product to be administered per day in the Investigational Product 
Accountability Log. Parents/legal guardians will be required to return the bottle containing study 
product to the investigator. Returned study product will be destroyed by the SPA according to 
the standard operating procedure (SOP) once its return has been documented. The study 
monitor will periodically check the amount of study product held by the investigator or 
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6.5 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product  
Parents/legal guardians will be instructed to track and record study product administration on 
the electronic diary and to return the study product bottle at the end-of-study follow-up visit. 
Subjects will be considered to have been compliant with study product if they have taken 70% of 
the intended regimen. 
6.6 
Concomitant Medications/Treatments 
Medication history will be obtained by interview of the parents/legal guardians. We will ask 
about previous antihistamines, decongestant, albuterol, or corticosteroid use during the past 7 
days and antibiotics use up to 3 months before enrollment. 
Use of select oral or nasal concomitant medications (antihistamines, decongestants, albuterol, 
antibiotics, corticosteroids, and analgesics) taken by the subject from the time of consent 
through the end-of-study follow-up visit or early termination, whichever occurs first, will be 
ascertained by parent/legal guardian interview at the end-of-study follow-up visit or early 
termination, whichever occurs first. Receipt of a systemic antibiotic while taking study 
medication will be recorded as this constitutes a secondary endpoint of the study. 
Medications that might interfere with the evaluation of the investigational product should not be 
used unless absolutely necessary. Medications in this category include: systemic 
corticosteroids, nasally administered decongestants or corticosteroids, and systemic 
medications containing decongestants, antihistamines, or corticosteroids. During participation in 
this study, subjects should not participate in any other clinical trial and should not receive any 
investigational drug or vaccine. The use of ibuprofen and acetaminophen is permitted. In the 
event of an allergic reaction to the assigned study product, subjects will be treated with 
clindamycin plus cefixime, or levofloxacin or a similar antibiotic, as clinically indicated using the 
results of the NP culture to guide therapy and without breaking the blind. 

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7 
STUDY SCHEDULE 
See Supplement A for the Schedule of Events table. 
7.1 
Screening – Day 1 
Parents/legal guardians of children presenting to a participating center with URI symptoms will be 
introduced to study staff by office personnel. The research staff will question the parent regarding 
the presence and characteristics of their child’s symptoms [duration of symptoms, course of 
symptoms (e.g., improving, staying the same, worsening), severity of symptoms (PRSS), history 
of allergic rhinitis, history of asthma]. If the provider’s clinical assessment does not then reveal 
another etiology that would exclude the child from participating (e.g., AOM, pneumonia, 
streptococcal pharyngitis, wheezing) informed consent will be sought from the parent/legal 
guardian. We will attempt to enroll consecutive children meeting eligibility criteria. We will maintain 
logs of eligible children who are not enrolled. 
7.2 
Enrollment/Baseline Visit (Entry Visit) – Day 1 
After obtaining written informed consent from the parent/legal guardian, we will gather information 
on the following potential predictors and confounders: demographic characteristics, risk factors 
(day care attendance, previous systemic antimicrobial use, exposure to household cigarette 
smoke), symptoms (type and duration, including some symptoms not included on the PRSS), past 
medical history (sinusitis, AOM, allergic rhinitis, asthma, pneumococcal vaccination), temperature 
and weight measurement (if not already taken for clinical care), and concomitant medications. 
Temperature will be measured using appropriate method according to the child’s age and parental 
preference (oral, rectal, axially, temporal, or tympanic). We will assess the nose and throat for 
facial tenderness and swelling. A nasopharyngeal swab will be obtained, when possible, and 
placed in transport media and sent to the Microbiology Laboratory-CHP for processing. In the 
event a nasopharyngeal swab is unable to be obtained, the study team will attempt to obtain a 
mid-turbinate nasal swab.When possible,the first dose of the study product will be given at the 
time of enrollment following randomization and monitoring of adverse events will begin. This will 
reduce variability due to delay in the initiation of therapy. We will ask parents/legal guardians to 
refrain from administering intranasal medications (e.g., corticosteroids, decongestants), and 
systemic medications containing antihistamines, decongestants or corticosteroids to their child for 
the duration of the study. We will assess whether the nasal discharge is colored. In our 
preliminary study (n=276), we showed that asking parents/legal guardians directly about the color 
of the nasal discharge (In the last 24 hours, was your child’s nasal discharge (mucus) yellow or 
green?) yielded information that was predictive of both the bacteria cultured from the nasopharynx 
(p=.006) and the findings of sinus radiographs (p=.003). Parental/legal guardian report of “white” 
discharge or physician examination of the anterior nares or nasal turbinates for colored discharge 
was not similarly informative. As an additional method of assessing color, we will utilize a color 
chart (with 4 colors: green, yellow, white, clear) and ask parents/legal guardians to identify the 
color that most closely resembles their child’s nasal discharge. Nevertheless, based on our strong 
preliminary data, and based on the fact that the assessment of nasal discharge using a color chart 
is unlikely to be practical in a busy clinical practice, asking parents/legal guardians whether their 

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child’s nasal discharge was yellow or green will remain the primary method of defining “colored 
nasal discharge”. 
7.3 
Follow-up eVisits – Days 2-11 
Diary – Parents/legal guardians will be asked to complete the PRSS electronically once 
daily–at the time of the evening dose of the study product and when their child is able to provide 
active input–from the day of enrollment (Day 1) to Day 11. Parents/legal guardians will be 
instructed to record each dose of study product given to the subject in the daily electronic diary. 
Suggested times for administration of study product will be 7:00 AM and 7:00 PM with a meal or a 
snack. Parents/legal guardians will be instructed on proper measurement and handling and 
storage of reconstituted study product. Once a day, we will send parents/legal guardians a text 
message or an email with a link to a secure website where they will be able to complete the 
PRSS. Versions for both a personal computer and a smart phone or tablet will be available. We 
will ensure that parents/legal guardians understand the process of completing the diary by having 
them complete a mock entry either on their personal cell phones or on the research PC or tablet 
at the enrollment visit. We will reimburse parents/legal guardians $5 for every diary entry 
completed on the day the alert was sent ($55 total).Parents/guardians, who complete all diary 
entries, will be reimbursed an additional $30. Parents/legal guardians who do not have access to 
the internet will be loaned a phone or tablet (with limited functionality) which they can use to 
complete the entries. We will reimburse parents/legal guardians $50 at the time of the end-of-
study follow-up visit and to encourage the return of the study phone or tablet if one was loaned 
The diary will also ask about medication compliance (adherence assessment), adverse events, 
and the overall degree of change from the previous day (on a 7-point scale) (symptom 
assessment). In a survey of 108 parents/legal guardians attending our inner-city clinic, 85% 
reported having a cell phone with a data plan. The proportion of parents/legal guardians with 
access to the internet will likely be higher at the other study sites. 
Phone calls – Every morning (including weekends), we will call or text parents/legal 
guardians whose evening PRSS score is missing. If the PRSS score is missing, this information 
will be collected over the phone or the parents/legal guardians will be provided a text with a link to 
complete the missing diary entry.  
7.4 
Final Study Visit (End-of-Study Follow-up Visit) – Days 12 to 18 
Parents/legal guardians and their children will be asked to return once during Days 12 to 18 for a 
routine follow-up evaluation. At this visit, the PRSS will be completed and parents will be 
questioned regarding the child quality of life. A nasopharyngeal swab will be  obtained,when 
possible, and placed in transport media and sent to the Microbiology Laboratory-CHP for 
processing. In the event a nasopharyngeal swab is unable to be obtained, the study team will 
obtain a mid-turbinate nasal swab. We will ask about adverse events, interim medical history 
including visits to other health care providers, and concomitant medications. A phone call, email 
or text message will be sent 1 to 2 days before the end-of-study follow-up visit to confirm the time 
of the appointment. If the patient is unable to come to the end-of-study follow-up visit, a visit to the 
home will be offered. If this is not possible, we will, to the extent possible, obtain information that 
was to be gathered at the Final Study Visit by phone or email.  

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7.5 
Unscheduled Visit (Interim (Sick) Visit) 
If a child’s PRSS score is not improving as expected, or if a parent is concerned about their child, 
an interim evaluation will be scheduled, usually on the same day. If the parent/legal guardian is 
unable to come to the office, a home visit may be offered. If the child cannot be seen and 
assessment of the child’s symptoms by phone indicate that the child is not acutely worsening and 
no new symptoms are reported, an antibiotic may be started without an evaluation. A study team 
member will be available 24 hours/day, 7 days/week via cellular phone. Children failing study 
product will be treated with clindamycin plus cefixime, amoxicillin-clavulanate potassium, 
levofloxacin, or a similar antibiotic, as clinically indicated and without breaking the blind. The 
results of the nasopharyngeal culture may be used to guide therapy. The following procedures 
may be performed at this visit: interim medical history including visits to other health care 
providers and concomitant medications collection, temperature measurement, face/nose 
assessment, PRSS score, and adverse events monitoring. Temperature will be measured using 
appropriate method according to the child’s age and parental preference (oral, rectal, axially, 
temporal, or tympanic). 

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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
Medical History: Will be obtained by interview of the parents/legal guardians. Parents/legal 
guardians will be queried regarding demographic characteristics, risk factors (day care 
attendance, exposure to smokers in the house), symptoms (type and duration, including some 
symptoms not included on the PRSS), and past medical history since birth (sinusitis, allergic 
rhinitis, asthma, and medications used to treat these) at the baseline visit. We will also ask 
parents/legal guardians to assess the severity of their child’s symptoms using a visual analog 
scale anchored at “very mild” and “very severe”. At the final end-of-study follow-up 
visit, we will ask parents to complete the PRSS, to answer question about visits to other 
providers, missed work, quality of life, and the need to make alternate daycare arrangements, 
and about adverse events. 
Medication History: Will be obtained by interview of the parents/legal guardians. We will ask 
about previous antihistamines, decongestant, albuterol, or corticosteroid use during the past 7 
days and antibiotics use up to 3 months before enrollment. We also track the use of these same 
medications along with analgesic medication through the end-of-study follow-up visit or early 
termination, whichever occurs first. Receipt of a systemic antibiotic while taking study 
medication will be recorded as this constitutes a secondary endpoint of the study. The use of 
these medications will be ascertained by parent/legal guardian interview at the end-of-study 
follow-up visit or early termination, whichever occurs first. 
Vital Signs: Temperature and weight will be measured at enrollment/baseline visit and the 
interim (sick) visit (if not already taken for clinical care). Temperature will be measured using 
appropriate method according to the child’s age and parental preference (oral, rectal, axially, 
temporal, or tympanic). 
Limited assessment of face and nose: At the baseline and unscheduled interim (sick) visit, a 
targeted assessment of the face and nose using standardized methods will be performed by 
appropriate study personnel. 
Diary: The PRSS will be administered by parents/legal guardians every evening as an electronic 
diary. In addition to the PRSS score, the diary will track compliance with study product, the 
frequency and the consistency of bowel movements, and a global assessment of health. The 
critical data for symptom resolution is during days 2-11, but we have given parents the 
opportunity to record the information from day 1 in order to establish the habit of recording in the 
diary. 
8.2 
Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations 
At the enrollment/baseline and final study visit, a nasopharyngeal sample may be obtained from 
one nostril using a sterile, flexible, thin, flocked swab. Compared to Dacron swabs, flocked swabs 
are better tolerated and have a higher yield for bacteria54,55 and viruses.56-58 The tip of the nose 

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will be raised and the swab introduced gently along the floor of the nasal cavity, close to the nasal 
septum, until the pharyngeal wall is reached. If any obstruction is encountered, the sample will be 
taken from the other nostril. All investigators will be trained on this procedure before to the onset 
of the study (see protocol-specific Manual of Procedures). We will cut the tip of the swab with a 
pair of sterile scissors into a cryovial containing RLT and this will be stored for future studies of 
RNA expression. The remainder of the swab will be placed into Amies and will be refrigerated (2-
8˚ C) until it can be transported (on ice) to the Microbiology Laboratory at Children’s Hospital of 
Pittsburgh (within 48 hours). Two types of culture plates will be used initially: trypticase soy 5% 
sheep blood agar and chocolate agar.  Cultures will be incubated overnight at 37°C with 5% CO2. 
If no growth is present after overnight incubation, the culture will be re-incubated for an additional 
24 hours. Identification of S. pneumoniae, H. influenzae, M. catarrhalis and Streptococcus 
pyogenes will be performed using standard semiquantitative techniques. For isolates thought to 
be H. influenza that will be subcultured on a Haemophilus ID Quad plate.  These isolates will be 
typed and if found to be non typeable, confirmed to be H. influenza by PCR.  In addition, we will 
test for b-lactamase production using a cefinase test on selective agar. Isolates considered to be 
M. catarrhalis will undergo subculture and identification will be confirmed using the Remel 
Catarrhalis Test Disk. Isolates considered to be S. pneumoniae will undergo subculture on a TSA 
blood agar plate. Susceptibility testing will be done on all isolates using the Vitek system. Isolates 
will be considered nonsusceptible to penicillin according to the most current guidelines from the 
Clinical Laboratory Standards Institute (CLSI). Microdilutional broth susceptibility testing will be 
performed on all penicillin non susceptible isolates. All pneumococcal isolates will be typed using 
gene-based typing methods. 
8.2.2 Special Assays or Procedures 
Not applicable. 
8.2.3 Specimen Preparation, Handling, and Shipping 
8.2.3.1 Instructions for Specimen Preparation, Handling, and Storage 
All clinical microbiological samples (NP swab  and MT swab specimens) obtained from all study 
participants enrolled at all participating clinical study sites will be processed at CHP according to 
guidelines established by the Microbiology Laboratory. This laboratory will identify all organisms 
cultured from the samples. Instructions for specimen preparation, handling, and storage are 
included in the Laboratory Plan. 
8.2.3.2 Specimen Shipment 
NP swab (or MT swab) specimens may be collected at the entry visit (Day 1) and the follow-up 
visit (Day 12-18). Specimens will be placed in a transport tube with a study label. Specimens 
are transported to the Microbiology Laboratory at CHP at intervals of every 3 hours for CHP of 
UPMC sites. Specimens from PittNet PBRN sites will be refrigerated and sent via courier to the 
Microbiology Laboratory at CHP within 48 hours. Specimens from all other sites will be mailed 
on the day of collection to the Microbiology Laboratory at CHP. Specimen shipments will be 
recorded in a specimen-tracking log. 
 

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The NP or MT swab specimens will be sent to: 
 
Children’s Hospital of Pittsburgh  
 
Microbiology Laboratory B228 
 
4401 Penn Avenue 
 
Pittsburgh, PA 15224 
Instructions for specimen shipment are included in the Laboratory Plan. 
 

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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
We will track common and important adverse events linked with the study product [i.e., Protocol-
Defined Diarrhea (PDD), generalized rash, and bacterial resistance], any adverse event, which 
requires more than minimal medical intervention (see below for definitions), and all serious 
adverse events. 
Because the study product is approved for use for children with sinusitis, we will only track 1) 
common or important adverse events linked with the study product (PDD, generalized rash), 2) 
severe adverse event (AEs which require more than minimal medical intervention, Table 4, 
below), and 3) serious adverse events (see section 9.2.3). PDD will be defined by the 
occurrence of three or more watery stools in 1 day or two watery stools daily for at least 2 days. 
The occurrence of these AEs will be recorded from the first study intervention, Day 1 
(enrollment), through the end-of-study follow-up visit. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
9.2.1 Adverse Events 
Adverse Event (AE): ICH E6 defines an AE as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product regardless of its causal 
relationship to the study treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of medicinal (investigational) product. The occurrence of an AE may come to the 
attention of study personnel during study visits and interviews of a study recipient presenting for 
medical care, or upon review by a study monitor. FDA defines an AE as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related. 
AEs not meeting the protocol-defined criteria for SAEs will be captured on the appropriate 
electronic case report form (eCRF).  Information to be collected for non-serious AEs includes 
event description, date of onset, licensed study physician’s assessment of severity and 
relationship to study product and alternate etiology (if not related to study product) (assessed 
only by those with the training and authority to make a diagnosis and listed on the Form FDA 
1572 as the site principal investigator or sub-investigator), date of resolution of the event, 
seriousness and outcome.  AEs occurring during the collection and reporting period will be 
documented appropriately regardless of their relationship to the study product. All recorded AEs 
will be followed to adequate resolution. Any medical condition that is present at the time that the 
subject is screened will be considered as baseline and not reported as an AE. However, if the 
severity of any pre-existing medical condition increases at any time during the study, it will be 
recorded as an AE. AEs must be graded for severity and assessed for relationship to study 
product (see definitions below).  Adverse events characterized as intermittent require 

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documentation of onset and duration of each episode.  The start and stop date of each reported 
AE will be recorded on the appropriate eCRF. Bacterial resistance will be reported based on the 
report from the laboratory.  
Severity of Event:  AEs will be assessed by a licensed study physician listed on the Form FDA 
1572 as the site principal investigator or appropriate sub-investigator.  The severity of non-
serious AEs will be assessed according to the scale below: 
• 
Mild: events require minimal or no treatment and do not interfere with the subject’s daily 
activities. 
• 
Moderate: events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe: events interrupt a subject’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
Examples of the types of non-serious AEs that will be collected (contained within the heavy 
lines) and AEs that will not be collected (gray font and marked by an asterisk) are shown in 
the Table below. 
Table 4. Procedure for Recording of Non-Serious Adverse Events 
 
Non-Serious Adverse Events 
 
Mild  
Moderate 
Severe 
Rash 
 
*Localized  
Generalized and moderate  Generalized and 
severe (e.g., severe 
urticaria; serum 
sickness; Stevens-
Johnson Syndrome) 
Diarrhea 
*Loose stools 
3 or more watery stools in 
1 day or 2 watery stool 
daily for at least 2 days 
(i.e., PDD) 
Diarrhea requiring 
rehydration therapy 
and is incapacitating 
All other  
Adverse Events 
*Requires 
minimal or no 
treatment and 
does not 
interfere with 
daily activities 
*Requires some treatment 
and may interfere with 
daily activities  
Requires systemic drug 
therapy and is clearly 
incapacitating 
Bacterial 
resistance 
N/A 
N/A 
All bacterial resistance 
will be collected 
*AEs that will not be collected 
Relationship to Study Products: The study physician’s assessment of an AE's relationship to 
the study product is required prior to unblinding and is part of the documentation process, but it 

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is not a factor in determining what is or is not reported in the study. Factors to consider in 
determining a causal relationship include whether: (1) the event is described in the product 
insert; (2) a temporal relationship exists between the event and administration of study product; 
(3) a possible alternative etiology has been identified; and (4) it is biologically plausible that the 
event may be related to the product. If there is any doubt as to whether a clinical observation is 
an AE, the event should be reported. In a clinical trial, the study product must always be 
suspect.  The relationship to study product must be assessed for AEs using the terms: related 
or not related.  The following guidelines will be used in this assessment: 
• 
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. 
9.2.2 Reactogenicity 
Not applicable. 
9.2.3 Serious Adverse Events 
Serious Adverse Event (SAE): An adverse event or suspected adverse reaction is considered 
“serious” if it results in any of the following outcomes: 
• 
Death, 
• 
a life-threatening adverse event*, 
• 
inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• 
a congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
* Life-threatening adverse event.  An adverse event is considered “life-threatening” if, in the 
view of either the site principal investigator or sponsor, its occurrence places the patient or 
subject at immediate risk of death.  It does not include an adverse event that, had it occurred in 
a more severe form, might have caused death. 

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All SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or appropriate sub-investigator. 
• 
Recorded on the appropriate SAE form and eCRF 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
• 
Reviewed and evaluated by the Independent Safety Monitor (ISM), Data and Safety 
Monitoring Board (DSMB), DMID, and the Institutional Review Board (IRB). 
9.2.4 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
NP specimens will be obtained for culture at baseline and follow-up for the identification of S. 
pneumoniae, H. influenzae, and M. catarrhalis. Detection of S. pneumoniae, H. influenzae, and M. 
catarrhalis in the nasopharynx will be considered a normal finding. 
Study product may need to be discontinued in subjects with a clinical adverse event, laboratory 
abnormality, intercurrent illness, or other medical condition such that continuation of study 
product would not be in their best interest. Randomization codes will not be broken at any time 
in the event of treatment failure unless deemed necessary for medical /emergency/safety 
reasons. These subjects will be asked to continue to record their symptoms on the PRSS on a 
daily basis and to return to the clinic for a routine end-of-study follow-up visit to be held once 
during Days 12 to 18. 
9.3 
Reporting Procedures 
Non-serious AEs occurring throughout the study-reporting period will be documented from the 
first study intervention, Day 1 (enrollment), through the end-of-study follow-up visit (Day 12-18) 
using the eCRF. 
SAEs occurring throughout the study-reporting period will be documented from the first study 
intervention, Day 1 (enrollment), through the end-of-study follow-up visit (Day 12-18) using the 
appropriate SAE form and eCRF. 
SAEs related to the study product will be reported to the principal investigators and IRBs 
immediately (within 24 hours of site awareness). Unexpected severe adverse reactions related 
to study product will be reported to the IRBs per local IRB guidelines and subsequently reported 
to the principal investigators. Line-item reports of all SAEs and a report of all recorded AEs will 
be submitted to the DSMB and DMID according to the frequency established in the DSMB 
charter. 
9.3.1 Serious Adverse Events 

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Any AE that meets a protocol-defined serious criterion will be submitted immediately (within 24 
hours of site awareness) on a 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) 
SAE FAX Phone Number: 1-800-275-7619 (US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, selected SAE data fields must also be entered into the central 
database. Other supporting documentation of the event may be requested by the DMID 
Pharmacovigilance Group and should be provided as soon as possible. 
The site will send a copy of the SAE report(s) to the ISM when they are provided to the DMID 
Pharmacovigilance Group.  The DMID medical monitor and clinical protocol manager will be 
notified of the SAE by the DMID Pharmacovigilance Group. The DMID medical monitor will 
review and assess the SAE for regulatory reporting and potential impact on study subject safety 
and protocol conduct. 
 
At any time after completion of the trial, if the investigator becomes aware of an SAE that is 
suspected to be related to study product, the investigator will report the event to the DMID 
Pharmacovigilance Group. 
9.3.2 Regulatory Reporting for Studies Conducted Under IND 
In consultation with DMID, the principal investigators will report any suspected adverse reaction 
that is both serious and unexpected. The principal investigators 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. The principal investigators 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. The principal investigators 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, the principal investigators 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, will be reported to the FDA at least annually in a summary format. 
9.3.3 Reporting of Pregnancy 
Not applicable. 

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9.4 Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be collected, assessed, and followed through resolution throughout the study-reporting 
period. 
SAEs will be collected, assessed, and followed through resolution even if this extends beyond 
the study-reporting period. 
Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate form 
and/or eCRF. 
9.5 
Halting Rules 
Further enrollment and study product administration will be halted for DSMB 
review/recommendation if any of the following are reported: 
• 
Any death occurs following study product administration that was not the result of trauma 
or accident. 
• 
Any subject develops brain abscess or bacterial meningitis. 
• 
Two subjects develop complications of sinusitis (e.g., orbital cellulitis, frontal bone 
subperiosteal abscess). 
If any of the halting rules are met following any subject receipt of study product, the trial will not 
proceed with the remaining enrollments or study product administration without a review by and 
recommendation from the DSMB to proceed. The University of Pittsburgh, IRBs and DMID 
retain the authority to suspend enrollment and/or study product administration during the entire 
trial, as applicable. 
9.6 
Safety Oversight (ISM plus DSMB) 
Safety oversight will be conducted by an external DSMB, which is an independent group of 
experts that reviews study data, monitors subject safety and advises DMID and the principal 
investigators. The DSMB will consist of at least three voting members with appropriate expertise 
to contribute to the interpretation of the data from this trial including a biostatistician experienced 
in statistical methods for clinical trials and a clinician with relevant expertise. 
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 this trial. To 
avoid any appearance of conflict of interest, it is critical that DSMB members not be involved in 
the study, have no vested interest in its outcome, have no ties to the study investigators and 
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The DSMB will review study progress and participant, clinical, efficacy, laboratory, and safety 
data at the following time points: 
• 
At specified times during the course of this trial as defined in the DSMB Charter. 
• 
At the time of the interim analysis (conducted after 344 subjects have been enrolled and 
completed follow-up). 
• 
Ad hoc when a halting rule is met, for immediate concerns regarding observations during 
this trial, or as needed. 
The DSMB will meet regularly to monitor the cumulative safety data during the period when 
participants are receiving study product and during the participant follow-up period. The DSMB 
will monitor the study according to the guidelines specified in the study protocol and the charter 
established at their initial meeting, unless the DSMB determines during the course of the trial 
that modification of the guidelines is in the best interest of this trial and its participants. Such a 
decision may be based on new information that emerges during the course of this trial (e.g., 
publication of the results of a similar trial), realization of inappropriate initial study assumptions, 
or the occurrence of an unanticipated scenario. 
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 and meetings will be defined in the 
charter. Procedural issues include: the board’s meeting frequency; the types and formats of 
reports it will receive from the DMSU, the policy on whether and how the members may be 
unblinded; what interim data (if any) may be released to the study investigators (e.g., overall AE 
rate); and how minutes will be taken and distributed. 
Before initiation of this trial, the DSMB will review the study protocol (particularly the specific 
outcome definitions), halting rules, the interim and final analysis plan, the procedures for 
recording and reporting SAEs, and the data and safety monitoring plan (including draft shells of 
safety reports and tables). The informed consent document/process also will be inspected to 
ensure that all required elements have been included in language understandable to 
parents/legal guardians of children to be enrolled in this trial. 
Study data will be reviewed by the DSMB per the charter for this study. The DSMB will review 
applicable data to include but not limited to study progress, enrollment, demographic, clinical, 
efficacy outcomes, laboratory and safety data which includes AE/SAEs, medical history, 
physical assessments, concomitant medications, compliance, and laboratory results (NP 
cultures). Interim statistical reports will be generated when 50% of patients have completed the 
study. Comparative results are presented to the DSMB in closed sessions attended only by 
voting members of the DSMB and by a representative of DMID. Additional data may be 
requested by the DSMB, and additional 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 may also be provided with expected and observed rates of the expected 
AEs in an unblinded fashion, and may request treatment assignment be unblinded for an 
individual subject if required for safety assessment.  The DSMB will review grouped and 
unblinded data in the closed session only. As an outcome of each review or meeting, the DSMB 

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will make a recommendation as to the advisability of proceeding with enrollment and study 
product administration (as applicable), and to continue, modify, or terminate this trial. 
DMID 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 this trial. 
The DMID Medical Monitor is empowered to stop study enrollment and study product 
administration if adverse events that meet the halting criteria are reported. The DMID Medical 
Monitor and the ISM will be responsible for reviewing SAEs in real time.  The DSMB will review 
SAEs on a regular basis and ad hoc during this trial. 
Independent Safety Monitor (ISM) 
ISMs are physicians with relevant pediatric expertise and whose primary responsibility is to 
provide timely independent safety monitoring. The ISM (one for each site) will not be directly 
involved in the trial, will not be under the investigators’ supervision, and will have no financial, 
intellectual, proprietary or professional interest in the outcome of the trial. An ISM with relevant 
sinusitis and/or pediatric infectious diseases expertise is assigned to each participating clinical 
study site, is in close proximity to the site and has the authority to readily access study 
participant records. The ISM reviews any SAE in real time and other AEs as needed and 
provides an independent assessment to the investigators and DMID. The ISM will not contact 
the DSMB directly. 

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10 
CLINICAL MONITORING 
10.1 Site Monitoring Plan 
Site monitoring will be conducted to ensure that human subject protections, study procedures, 
laboratory procedures, study intervention administration, and data collection processes are of 
high quality and meet DMID, University of Pittsburgh, and ICH E6 (GCP) guidelines and 
applicable regulations, and that this trial is conducted in accordance with the protocol, protocol-
specific MOP, and applicable standard operating procedures. 
Independent clinical study site monitoring will be conducted as detailed in the clinical monitoring 
plan. This will include on-site monitoring visits at standard intervals, or more frequently as 
necessary, throughout the study to oversee data collection, review source documentation, 
ensure GCP, protocol and regulatory compliance, and resolve data queries. 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 compliance. The monitor’s Clinical 
Research Associates (CRAs) will have reasonable access to the participating clinical study 
sites, study personnel, and all study documentation. CRAs will meet with participating clinical 
study site investigators to discuss any problems and actions to be taken and document visit 
finding and discussions. Clinical monitoring reports will be submitted to the principal 
investigators and DMID. 

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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
 
Hypothesis 1: Children not colonized with respiratory pathogens are unlikely to benefit from 
antimicrobial therapy. 
Hypothesis 2: Children without colored nasal discharge are unlikely to benefit from antimicrobial 
therapy. 
11.2 Primary and Secondary Analyses 
 
Primary 
• 
To determine whether the effect of antimicrobial treatment differs in predefined 
subgroups of children with acute sinusitis (i.e., to test for treatment subgroup 
interactions). Subgroups will be defined by the (1) presence vs. absence of 
nasopharyngeal (NP) colonization with respiratory pathogens (Streptococcus 
pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis), and (2) presence vs. 
absence of colored (yellow or green) nasal discharge. 
Secondary 
• 
To determine whether antimicrobial therapy is superior to placebo (i.e., to test for the 
overall effect) 
Tertiary 
• 
To evaluate compliance with study product 
• 
To assess adverse events associated with use of amoxicillin clavulanate, including the 
development of bacterial resistance 
• 
To compare resource utilization according to treatment strategy 
11.3 Analysis Populations 
 
11.3.1  
Intent-to-Treat Population (ITT) 
 
The ITT population will consist of all eligible randomized children with at least 1 diary entry. This 
population will form the basis for the primary and secondary efficacy analyses of study data as 
well as for the safety analyses. 
11.3.2        Per Protocol Population 
 
Children who receive 70% of the prescribed doses of study product (whether antibiotics or 
placebo) will comprise the per protocol population. This population will form the basis of 
secondary, supportive analyses of the efficacy and safety endpoints. 
11.4 Efficacy Assessments 
 

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The daily PRSS score over the first 10 days of therapy (Day 1 to 11) will be recorded by 
parents/legal guardians using an electronic tablet or a personal computer, a cell phone, or a 
tablet every evening. A routine end-of-study follow-up clinic visit will be held once during Days 
12 to 18 day. An interim visit will be scheduled if the PRSS score has not improved as expected, 
i.e. if child meets definition for treatment failure. 
11.4.1 Primary Efficacy Variable 
 
The PRSS score over the 10 days of therapy will serve as the primary efficacy variable because 
it represents the outcome that it is clinically most relevant. Clinicians prescribe antimicrobials for 
children with acute sinusitis under the assumption that it hastens the resolution of symptoms. 
Thus, to assess the degree of improvement and/or deterioration we chose a validated symptom 
score to serve as the primary efficacy variable. 
 
The PRSS (See Supplement B) consists of eight discrete items: runny nose, stuffy nose, 
daytime cough, nighttime cough, sleeping difficulty, trouble breathing through the nose, 
irritability, and being tired. Parents/legal guardians are asked to rate these symptoms, as 
“none”, “almost none”, “a little”, “some”, “a lot”, or “an extreme amount” with corresponding 
scores of 0 to 5. PRSS scores may thus range from 0 to 40. 
11.4.2 Secondary Efficacy Variables 
The secondary efficacy variables include: 
1) Treatment failure - Children who are not improving at the expected rate will be identified 
through daily monitoring of the PRSS scores by the study staff. These children will be 
seen by the study team and rescue medication will be prescribed, as clinically indicated. 
We will define treatment failure if any of the following conditions are met: 
a. Worsening at any time–total PRSS score increased by >20% from entry. 
b. No change by 48 hours–total PRSS score decreased by <2 points from entry 
(Day 1) to Day 3. 
c. Failure to improve significantly by 72 hours–total PRSS score decreased by 
<20% from entry (Day 1) to Day 4. 
d. PRSS decreased by <20% from enrollment on 2 consecutive occasions on Days 
5-11 
e. Still symptomatic (total PRSS score ≥50% of entry score) at the time of the end-
of-study follow-up visit (Days 12 to 18). 
2) Development of AOM (acute symptoms and a bulging tympanic membrane) on Days 1 
to 11. 
3) Receipt of an antibiotic (other than the assigned study product) for any indication on 
Days 1 to 11. 
11.5 Safety and Tolerability Assessments 
Safety and tolerability assessments include: 
1) Adverse events - The proportions of children experiencing certain adverse events will be 
compared. We will also track the duration of these adverse events. Diarrhea will be 

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defined as the occurrence of ≥3 watery stools in 1 day or 2 watery stools per day for 2 
consecutive days. This will be tracked in the daily diary. Changes in bacterial resistance 
from baseline to follow-up will be tabulated. 
2) Compliance - In the daily diary, we will ask parents/legal guardians to record whether 
they administered the doses of study product. Administration of ≥70% of the doses will 
be considered compliant. 
11.6 Statistical Analyses 
11.6.1 General Considerations 
Study data will be monitored on an ongoing basis by the Data Management and Statistical Unit 
in the Division of General Academic Pediatrics at the Children’s Hospital of Pittsburgh. Final 
cleaning and editing of the study database will be carried out after the last patient completes 
follow-up. Unblinding of treatment assignments will not be performed until the study data are 
cleaned, queries resolved, and database lock achieved. All changes to the study database will 
be documented. A permanent archive of the database will be maintained by the DMSU. 
 
A 2x2 factorial design, adjusted for multiple testing, will be used to detect interactions for the 
longitudinal outcome, where Factor A will be antibiotic-treated vs. placebo and Factor B will be 
either colored nasal discharge (yellow or green vs. clear) or nasopharyngeal colonization 
(positive vs. negative). 
 
All statistical tests will be two-tailed and conducted at global significance level of 0.05. For the 
primary efficacy analysis, the significance level for the final analysis will take into account the 
interim analysis. Sites with few children randomized may be pooled. Pooling of study sites will 
occur prior to unblinding. All programs used in the statistical analysis will be documented, 
tested, and archived. Archiving of statistical analyses at the DMSU includes the original written 
specifications for the analyses, any subsequent modifications, the computer program file, and 
the log, list and other output files produced by the program. The DMSU will use the most current 
version of SAS®. 
11.6.2 Interim Analysis 
Interim analysis will occur after 344 children have completed this trial. Type I error will be 
controlled using the method of Fleming, Harrington and O’Brien59 and testing will be conducted 
at significance levels of 0.005 and 0.048 at the interim and final analyses, respectively. If at 
least one of the tests for interaction is significant (i.e., if there is unequivocal evidence of 
treatment effect heterogeneity), the DSMB may consider recommending stopping this trial early. 
11.6.3 Subject Disposition 
The number of patients screened, randomized, withdrawn, and included in each analysis 
population (ITT, Per Protocol) will be reported by treatment group and according to site. In 
addition, the number of patients completing this trial and the reasons for patient withdrawal will 
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11.6.4 Baseline (Pre-Treatment) Analyses 
 
Demographic and baseline clinical characteristics will be presented by treatment group for all 
patients. For categorical variables we will report frequencies and percentages. For continuous 
variables we will report means and standard deviations. 
11.6.5 Concomitant Medication Use 
 
We will report the incidence of concomitant medication use according to treatment group using 
the ITT population. 
11.7 Efficacy Analyses 
11.7.1 Primary Efficacy Analysis of the Primary Efficacy Endpoint 
 
We present compelling preliminary data and extensive literature suggesting that the effect of 
antimicrobial therapy is likely to differ in certain subgroups of children with acute sinusitis. 
Accordingly,60-65 the primary efficacy analysis will assess the heterogeneity of treatment effect in 
subpopulations defined by presence of nasopharyngeal colonization and by the presence of 
colored nasal discharge (i.e., to test for interaction between treatment and subgroup effects). 
 
Interactions between treatment group and each subgrouping variable will be tested 
simultaneously. A Generalized Estimating Equations (GEE) model will be fit by including 
treatment by subpopulation interaction terms (adjusted for the baseline PRSS score) using the 
ITT dataset (see Section 6.8 for detailed multiple testing procedure).66 The regression analysis 
will be adjusted for clinical site as a potential confounding factor. 
 
Assumptions required for the validity of GEE will be assessed. These will include (i) the 
marginal mean of the response depends on a link function, (ii) the marginal variance depends 
on the marginal mean, and (iii) the correlation within subject depends on the marginal mean and 
other parameters. Therefore an appropriate link function will be chosen for the primary outcome 
and the goodness of fit of the model will be assessed. 
11.7.2 Secondary Efficacy Analysis of the Primary Efficacy Endpoint 
 
The secondary efficacy analysis will compare the PRSS scores during the first 10 days of 
therapy in the two treatment groups. This analysis is considered secondary because reporting 
the average treatment effect in the entire sample is not appropriate if the treatment effect in the 
subgroups we are considering is heterogeneous. GEE will be used to compare the marginal 
means adjusted for the baseline PRSS score and stratification variables using the ITT 
population. 
 
In addition, we will explore whether heterogeneous response to treatment is observed for other 
baseline variables, including worsening presentation, age, history of allergic rhinitis, and 
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exploratory, possibly providing information that may prove important in conducting future 
studies. 
11.7.3 Secondary Efficacy Analyses of the Secondary Endpoints 
 
Secondary efficacy variables include treatment failure, development of AOM, and receipt of an 
antibiotic. All of these are dichotomous variables. We will use the Cochran-Mantel-Haenszel 
test67-69 stratified by study site, using the ITT dataset. 
 
Additional analyses of the dichotomous secondary efficacy variables will use logistic regression 
to adjust for baseline covariates and other prognostic variables. 
11.8 Missing Data 
 
For children with missing values for the primary endpoint (no diary data available for a particular 
day), we will use only the days with non-missing values, which can be accommodated by the 
GEE method. Children with no diary entries will be excluded from the analysis. If a patient has 
missing data for a dichotomous secondary outcome variable, we will perform a sensitivity 
analysis first assuming that all such patients had the deleterious outcome (for instance, 
treatment failure) and then assuming that all such patients had a favorable outcome. 
 
The proportion of patients with missing data for each outcome variable will also be compared 
between treatment groups and the sensitivity to the missing data will be examined by 
reanalyzing the outcome using only the non-missing data. However, we are confident that the 
amount of missing data will be negligible because study procedures have been put in place to 
minimize missing data. 
11.9 Handling of Data from Withdrawn Subjects 
 
All such subjects who have at least 1 diary entry will be included in the intent-to-treat analysis 
population. 
11.10 Safety and Tolerability Analyses 
11.10.1 Compliance 
 
Compliance will be assessed by parental/legal guardians report on the daily diary. Compliance 
with study product will be defined as receipt of at least 70% of the expected doses. The 
proportion of patients who are compliant will be reported by treatment group. Treatment group 
differences in compliance will be assessed using a Cochran-Mantel-Haenszel test stratified by 
study site. 
11.10.2 Adverse Events 
 

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The number of patients with adverse events will be tabulated by treatment group. The number 
of patients experiencing each adverse event will also be summarized by severity and 
relationship to study drug. If an adverse event is reported more than once during the study 
period for a given patient, the greatest intensity will be presented in the tables. For summary 
tables, adverse events will be grouped by organ system. We will also track the duration of each 
reported adverse event. Diarrhea, a key and expected adverse event, will be defined as the 
occurrence of ≥3 watery stools in 1 day or 2 watery stools per day for 2 consecutive days, and 
will be tracked in the daily diary. The incidence of serious adverse events and study medication 
discontinuation due to adverse events will also be compared using Fisher’s exact test.70 Data 
listings and narratives will be provided for patients discontinuing treatment due to adverse 
events and patients with serious adverse events. 
11.10.3 Resource utilization 
 
We will collect data on direct costs (i.e., costs of visits to healthcare providers plus cost of 
medications) and indirect costs (e.g., travel costs). For direct costs, we will ask parents/legal 
guardians about the number and type of encounters with healthcare providers since enrollment. 
Similarly the types and duration of medication used will be ascertained. For indirect costs, we 
will ask parents/legal guardians about travel expenses, alternate child care expenses (for the 
patient and/or siblings), as well as time costs (e.g., for missed work). These assessments will be 
conducted at the time of the end-of-study follow-up visit. 
11.11 Sample Size Justification 
 
To estimate the sample size for this trial, we used estimates of within-subject correlation and 
grand variance from our preliminary data of children diagnosed with acute sinusitis. Because 
two simultaneous tests for interactions are being conducted, we used a two-sided significance 
level of 0.025 (50:50 split of the overall significance level of 0.05 for Bonferroni adjustment). 
 
Assuming an α of 0.025 (two-sided test), 344 evaluable children per treatment group will provide 
statistical power of 80% to detect an interaction effect size of 2.5 points in the mean symptom 
score (as measured by the PRSS) over the 10-day period assuming, as per results presented in 
Leon and Heo,71 that the required sample size to detect an interaction between treatment group 
and a subgroup would be four times that of a main effect of the same magnitude for a repeated 
measures outcome under a 2x2 factorial design. 
 
Even though we have calculated the sample size using the simple Bonferroni procedure, for the 
final analysis we will use a modified Bonferroni procedure for multiple testing, which is not as 
conservative for highly correlated test statistics.72 Under the Simes’ procedure, the null 
hypothesis associated with the smallest p-value will be rejected if the p-value is smaller than or 
equal to
 and one associated with the second smallest p-value will be rejected if the p-
value is smaller than or equal to
. Here 
is the appropriate significance level for the interim 
or definitive analysis. Specifically, the (ordered) observed p-values will be compared using 
0.0025 and 0.005 for the interim analysis and using 0.024 and 0.048 for the definitive analysis. 
/ 2
a
/ 2
a
/ 2
a

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating clinical study 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 participating clinical study site will permit 
authorized representatives of DMID, University of Pittsburgh or its designee, and appropriate 
regulatory and monitoring agencies to examine (and when required by applicable law, to copy) 
clinical trial records for the purposes of quality assurance reviews, audits, monitoring and 
evaluation of the study safety and progress. These representatives will be permitted access to 
all source data. All sites use certified, comprehensive Electronic Health Record (EHR) systems 
requiring privacy and security compliance and HIPAA and institutional policies addressing 
unauthorized access to the EHR systems; these policies preclude external representatives 
listed in this protocol from accessing the EHR. However, paper copies of the respective EHR 
system documentation may be provided to the monitors for review. 
 
Web-based electronic case report forms (eCRFs) will be the source documents for data 
collected during the study visits. These forms will be accessible from all study sites using a 
secure website managed by the DMSU. The data system includes features such as password 
protection, automatic time/date stamps, and automatic range checks that will identify data that 
appear inconsistent, incomplete or inaccurate. Electronic forms facilitate the generation of clean 
datasets by guiding investigators through the data collection process in such a manner as to 
display only questions and screens that are appropriate for the particular subject, thus 
minimizing the possibility of incorrect entries. An electronic audit trail of all changes will be 
maintained by the system (i.e., by recording old vs new value, date, time and reason for 
change). The database also performs an important tracking function by monitoring such 
parameters as missed follow-up appointments to ensure that the required data collection 
instruments are administered within the time constraints dictated by the study protocol. All files 
will be backed-up daily and archived weekly. 
Additional source documents include the patient’s medical record (i.e., for children who are 
prescribed another antibiotic while on study product), and laboratory reports (entered into the 
eCRF by the staff at the Microbiology Laboratory at CHP). 
 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the participating clinical study 
sites are responsible for conducting routine quality assurance (QA) and quality control (QC) 
activities to internally monitor study progress and protocol compliance. 
The principal investigators will provide direct access to all participating clinical study sites, 
source data/documents, and reports for the purpose of monitoring and auditing by DMID and 
University of Pittsburgh or its designee, and inspection by local and regulatory and authorities. 
The principal investigator will ensure all study personnel are appropriately trained and 
applicable documentation is maintained on site. 
The DMSU will implement quality control procedures beginning with the data management 
system and generate data quality control checks that will be run on the central database. Any 
missing data or data anomalies will be communicated to the participating clinical study site(s) for 
clarification and resolution. Monitoring of the day-to-day quality of the trial will be conducted by 
the Data Manager. 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The investigators will ensure that this trial is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46, 21 CFR 
50 and 56, and the ICH E6; 62 Federal Regulations 25691 (1997), if applicable. Each 
investigator’s institution will hold a current Federalwide Assurance (FWA) issued by the Office 
for Human Research Protections (OHRP) for federally funded research. 
14.2 Institutional Review Board 
An IRB registered with OHRP will review and approve the protocol and informed consent form 
prior to commencement of subject recruitment at each site. 
Prior to enrollment of subjects into this trial, the approved protocol and the informed consent 
form will be reviewed and approved by the appropriate IRBs listed on their FWA. 
The responsible official for the IRB will sign the IRB letter of approval prior to the start of this trial 
and a copy will be provided to the University of Pittsburgh and DMID. The IRB FWA number will 
be provided to the University of Pittsburgh and DMID. 
All amendments to the protocol or informed consent form will be written by the sponsor, 
approved before they are placed into use, provided to the investigators for submission to their 
IRBs, and a copy of the signed IRB letters of approval will be provided to the University of 
Pittsburgh and DMID. 
14.3 Informed Consent Process 
The participating clinical study site investigators will choose subjects in accordance with the 
eligibility criteria detailed in Section 5. The investigator will not exercise selectivity so that bias is 
prevented.  Before any study procedures are performed, the subject’s parent/legal guardian 
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 the subject’s parent/legal guardian 
agreeing to have their child participate in this trial and continuing throughout the subject’s study 
participation. Before any study procedures are performed, the subject’s parent/legal guardian 
will receive a comprehensive explanation of the study procedures and study 
interventions/products (antibiotics and placebo). This will include the nature and risks/benefits of 
this trial, alternate therapies, any known AEs, the investigational status of the components, and 
the other elements that are part of obtaining proper informed consent. The subject’s parent/legal 
guardian will also receive a detailed explanation of the proposed use and disclosure of their 
protected health information. The subject’s parent/legal guardian will be allowed sufficient time 

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to consider participation in this trial, after having the nature and risks of the study explained to 
them, and have the opportunity to discuss this 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 (antibiotics and 
placebo), study procedures, risks and possible benefits will be given to the subject’s parent/legal 
guardian. The informed consent form will not include any exculpatory statements.  Informed 
consent forms will be IRB-approved and the subject’s parent/legal guardian will be asked to 
read and review the appropriate document. Upon reviewing the appropriate document, the 
participating clinical study site investigator (or designee) will explain the research study to the 
subject’s parent/legal guardian and answer any questions that may arise. The subject’s 
parent/legal guardian 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 study, including administering study product. The subject’s parent/legal 
guardian will be given a copy of all informed consent forms that they sign. 
By signing the informed consent form, the subject’s parent/legal guardian agrees to have their 
child complete all evaluations required by this trial, unless the subject’s parent/legal guardian 
withdraws their child voluntarily, or their child is withdrawn or terminated from this trial for any 
reason. 
The rights and welfare of the subjects will be protected by emphasizing to the subject’s 
parent/legal guardian that the quality of their child’s medical care will not be adversely affected if 
they decline to have their child participate in or withdraw their child from this trial. 
Some children in this trial may be developmentally capable of providing assent. If so, this will be 
documented on the informed consent document. 
The University of Pittsburgh will provide the participating clinical study site investigators, in 
writing, any new information that significantly impacts the subjects' risk of receiving the 
investigational product.  This new information will be communicated by the participating clinical 
study site investigators to the subject’s parent/legal guardian who consent to participate in this 
trial in accordance with IRB requirements.  The informed consent document will be updated and 
the subject’s parent/legal guardian will be re-consented per IRB requirements, if necessary. 
Study personnel may employ IRB-approved recruitment efforts prior to obtaining the subject’s 
parent/legal guardian consent if a patient-specific screening consent is on record or if the IRB 
has agreed that chart review is allowed without a fully executed screening consent.  In cases 
where there is not a patient-specific screening consent on record, site clinical staff may pre-
screen via chart review and refer potential subjects to the research staff; however, before any 
study procedures are performed to determine protocol eligibility an informed consent form must 
be signed. 
14.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
This trial will be conducted in children aged 2 to 12 years, an age group that experiences the 
highest incidence of acute sinusitis. Children who meet eligibility criteria will be entered in this 

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trial without regard to sex, religion, or ethnic background and it is anticipated that enrollees will 
be divided approximately equally between boys and girls. We will recruit and enroll children who 
are representative of the sex, racial, and ethnic distribution of patients with acute sinusitis at the 
participating clinical study sites. No subject will be included or excluded on the basis of sex, 
race or ethnicity. Self-reporting of ethnicity and race using two separate questions will be used 
to identify demographic information as required by OMB Directive 15. 
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 site principal investigator, their study personnel, the sponsor, and 
their agents.  This confidentiality is extended to cover testing of biological samples, in addition to 
the clinical information relating to participating subjects. 
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 clinical study sites as part of this trial (other than a subject’s medical records) will 
be kept confidential by the investigators and their study personnel to the extent permitted by 
law. This information will not be used by the investigators or their study personnel for any 
purpose other than conducting this trial. These restrictions do not apply to: (1) information which 
becomes publicly available through no fault of the investigators or their study personnel; (2) 
information which is necessary to disclose in confidence to an IRB solely for the evaluation of 
this 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 study 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 investigators, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this study. The participating clinical study 
sites will permit access to such records. 
All paper records containing identifying information will be kept in locked files accessible only to 
the investigators and their study personnel and unlocked only while study personnel are working 
with the files. To ensure that confidentiality is maintained, the study coordinator will conduct 
inspections of the relevant premises at random times, usually weekly. Information regarding 
individual subjects will be kept private and shared only with the IRB, DSMB, the investigators, 
their study personnel, and the sponsor(s) and their agents. 
Clinical and laboratory data will be entered into a 21 CFR Part 11-compliant Internet eCRF 
provided by the University of Pittsburgh Center for Research on Health Care (CRHC). The data 
management system includes password protection, automatic time/date stamp and internal 

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quality checks, such as automatic range checks that occur in real time to identify data that 
appear inconsistent, incomplete or inaccurate. 
The respective information technology (IT) departments at each site will take all necessary 
steps to protect the confidentiality, integrity, and availability of all information assets on the 
computer network from unauthorized access while providing the mechanisms to grant, monitor, 
modify and remove access as required. At CHP, for example, users are authorized to access 
CHP’s IT resources based on roles and responsibilities necessary to perform the functions of 
their job. Access is granted based on what is minimally necessary for job completion. At all 
participating clinical study sites computer user accounts and passwords are used to uniquely 
identify and authenticate a user to a computer system or application. Accessing a computer 
application or system with a username and password is equivalent to the user’s signature. 
Additional efforts at the CRHC include limiting access to areas containing electronic confidential 
information. This includes monitoring the movement of people, equipment, and supplies into or 
out of the areas containing confidential information. The CRHC requires card access or pre-
approved visitor sign-in. Physical controls for the data center include: 
• 
Locked doors with restricted, logged, card key access 
• 
Video surveillance monitored by security and public safety personnel 
• 
Raised floor 
• 
Heat, smoke, and water detection 
• 
Environmental controls for heat and humidity 
• 
Fire suppression 
• 
Supporting utilities monitored by facilities personnel 
Further, the CRHC’s network is protected via an intrusion detection system (Solutionary) that 
protects against malicious code, denial of service attacks, and viruses. Interception of data 
transmission and electromagnetic interception are addressed by domain-based policies that 
manage data securely with security standards of IPsec, VPN, SSH, and PGP encryption. 
Each participating clinical study site computer must be compliant with basic standards to be 
granted access to the system. All participating clinical study site computers must be protected 
by an institutional firewall or local firewall software. Each computer must also be protected by 
local anti-virus and anti-spam software. These standards are verified through an authorization 
process overseen by the CRHC. At each participating clinical study site, each protocol team 
member shall only be assigned one unique account for each computer system or application. 
Passwords shall consist of seven or more characters and contain characters from three of the 
following four categories: capital letters (A through Z); lowercase letters (a through z); numbers 
(0 through 9); and symbols (!, $, #, %, @). Computer systems or applications shall automatically 
inform the account holder when a password change is required. New computer accounts shall 
be created with a one-time password that requires the user to establish a unique password 
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In the event that a breach is suspected, all potentially compromised account passwords will be 
immediately changed, and the appropriate help desk will be notified to investigate the potential 
security breach. 
To protect against data loss, each participating clinical study site will adhere to the CRHC and 
CHP data backup and recovery plans, which include procedures for creating and maintaining 
retrievable exact copies of information, programs, and operating systems. The plan covers: 
• 
Regular back-ups 
• 
Secure off-site storage of tapes and documentation 
• 
Regular testing of backup media 
• 
Incident response procedures 
• 
Disaster recovery plans with procedures for restoring lost information 
• 
Emergency mode of operation plan that contains procedures protecting electronic 
information while operating in an emergency situation 
• 
Testing and revision plan that contains procedures for periodic testing and revisions of 
the contingency plans. 
Any publications or presentations resulting from this work will not identify participants by name, 
but will only present aggregate data. 
14.6 Costs, Subject Compensation, and Research Related Injuries 
 
There will be no costs to the subject or their parent/legal guardian for the participation in this 
trial. Subjects’ parents/legal guardians may be compensated for the participation in this trial. 
Compensation will be in accordance with the local IRB’s policies and procedures, and subject to 
IRB approval. Parents/legal guardians will be reimbursed at each visit for their time and 
expenses, according to the local standards and IRB approval. 
We will reimburse parents/legal guardians $30 for the Enrollment/Baseline visit, and $5 for 
every diary entry completed on the day the alert was sent ($55 as well as an additional $30 if all 
diary entries are completed). Parents/legal guardians, who agreed to the nasal swab, will 
receive $20 at enrollment.  Parents/legal guardians who do not have access to the internet will 
be loaned a phone or tablet (with limited functionality) which they can use to complete the 
entries. We will reimburse parents/legal guardians $30 at the time of the end-of-study follow-up 
visit and to encourage them to return the study phone or tablet if one was loaned to them. If a 
second NP swab (or MT swab)is obtained at the child’s final study visit, we will reimburse the 
participant $20 for their time. In the event a subject is unable to return for their final study visit, 
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When needed, based on time of the year and climate conditions, taxicabs or “gas cards” may be 
used to facilitate transportation. Parents will receive free parking for each study visit, as 
applicable per site. 
Parents/legal guardians will be encouraged to contact the Principal Investigator if they believe 
that the research procedures have resulted in an injury to the subject. Emergency medical 
treatment for injuries solely and directly related to participation in this research study will be 
provided to participants. The insurance provider may be billed for the costs of this emergency 
treatment, but none of those costs will be charged directly to the participant. If the research-
related injury requires medical care beyond this emergency treatment, parents/legal guardians 
will be responsible for the costs of this follow-up care. No plan exists for any additional financial 
compensation. 
14.7 Study Discontinuation 
In the event that this trial is discontinued, enrolled subjects will continue to be followed until the 
end-of-study follow-up visit. Subjects with ongoing medical issues that require further follow-up 
will be referred to their physician. No further study products will be administered. 
14.8 Future Use of Stored Specimens 
 
Subjects or parent(s)/legal guardian(s) will have agreed to allow their NP sample and the 
organisms isolated from it to be used for future research studies including studies of bacterial 
genomics in the consent form. Samples will be stored indefinitely in the Microbiology Laboratory 
or at a central clinical storage facility and may be shared with investigators at the participating 
clinical study site and other investigators at other institutions. 
 
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) with a unique tracking number to protect subject 
confidentiality. 
 
There are no benefits to subjects in the collection, storage and subsequent research use of 
specimens. Reports about future research done with subjects’ samples will NOT be kept in their 
health records. 
 
If the subject or parent/legal guardian withdraws from the study, samples may still be used for 
this research. 

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15 
DATA HANDLING AND RECORD KEEPING 
The investigators are responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported. 
The eCRF will be developed by the DMSU as the source document to record and maintain data 
for each subject enrolled in the trial. Data reported in the eCRF should also be consistent with 
other source documents (laboratory reports), or the discrepancies should be explained. 
Any other source documents will be completed in a neat, legible manner to ensure accurate 
interpretation of data. When making changes or corrections, the original entry will be crossed 
with a single line, initialed and dated, without obliterating the original entry. The DMSU will 
provide guidance to investigators on making corrections to the eCRF or other source 
documents. 
15.1 Data Management Responsibilities 
All source documents will be reviewed by the clinical team and data entry personnel, who will 
ensure that they are accurate and complete. Adverse events must be assessed for severity and 
causality, and reviewed by the participating clinical study site investigator or designee. 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site investigator. During the trial, the investigators must maintain 
complete and accurate documentation for the study. 
The DMSU will be responsible for data management, quality review, analysis, and reporting of 
the trial data, including uploading results to the National Library of Medicine (NLM) database. 
The DMSU will manage data by developing checks on the central database for logical 
inconsistencies and reports for the participating clinical study sites, including recruitment, 
retention, missing forms, subject follow-up visit schedules, and treatment adherence. 
The DMSU can generate reports, including data quality and compliance information. Information 
on form submission and completeness will be available through the central database. 
Information will also be available to chart protocol progress, including recruitment and retention, 
schedule of upcoming patient visits, and quality of the data obtained. Other specialized reports 
may also be developed. 
Study personnel can query data from the central database in real-time and generate customized 
reports displaying current data for their clinical study site. DMID will be provided with read only 
access to the central database in real-time. If necessary, study and data entry and management 
personnel can view the same information simultaneously when troubleshooting a data issue. 
15.2 Data Capture Methods 
Screening logs of eligible and enrolled subjects will be maintained to detect the possibility of 
selection bias. The University of Pittsburgh Center for Research on Health Care eCRF will be 
accessible from participating clinical study sites using a secure Internet connection. The data 

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management system will present study site personnel with a readily available and 
comprehensive set of data management tools to perform data entry and routine processes by 
displaying information regarding forms that have been received, forms that are due, and forms 
that are late. The eCRF incorporates automatic edit checks that serve to prevent errors and 
substantially reduce time to clean data. 
Data obtained during the study visits will be entered directly into the eCRF which makes the 
eDMS the source document for this information. These data include clinical data (including 
AE/SAEs, concomitant medications, physical assessments, and diaries) and laboratory data 
(NP results). These data will be entered into a 21 CFR Part 11-compliant Internet eCRF 
provided by the University of Pittsburgh Center for Research on Health Care. The data 
management system includes password protection, automatic time/date stamp and internal 
quality checks, such as automatic range checks that occur in real time to identify data that 
appear inconsistent, incomplete or inaccurate. This will allow for ongoing and rapid query 
resolution and locking of the database at the close of the trial. 
Some limited additional information may need to be gathered from the EHR, in particular, as it 
relates to children who are seen by non-study providers and prescribed antibiotics while 
receiving study product. Clinical data from the off-site visits e.g., emergency department visits, 
participant primary care visit, etc., will be entered directly from the source documents. In this 
circumstance, the paper documents received from the provider will be considered the source 
documents.Types of Data 
Data for this study will include clinical, efficacy, safety, and laboratory data gathered in the 
eCRF. We will also obtain records of medical encounters at other facilities (if needed to 
document reasons for subject receiving another antibiotic during the study). 
15.3 Timing/Reports 
Study data will be reviewed by the DSMB per the DSMB charter for this study. Safety summary 
reports may be generated for this purpose. 
An Interim Report for DSMB review will be prepared by the DMSU after 344 subjects have been 
enrolled and completed follow-up. These reports will contain the most up-to-date data permitted 
by the timeframe necessary for the DMSU to prepare and review the analyses. Reports will 
usually consist of two parts, corresponding to the open and closed sessions of the DSMB 
meeting, and include an assessment of the progress of the trial, including recommendations on 
whether it should continue or be terminated or modified. Only the DSMB members (and 
designated representatives from DMID) will receive copies of the closed session report. The 
reports will be sent by the DMSU to the DMID for distribution to the DSMB members at least 14 
business days prior to a scheduled meeting. Safety and efficacy results will be presented by 
treatment group using randomly-assigned labels for the two treatment groups. 
The Clinical Study Report will be completed when all primary and secondary endpoint data are 
available. 

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15.4 Study Records Retention 
Study documents (records and documents pertaining to the conduct of this trial, including 
eCRFs, informed consent forms (except for future use informed consent forms), laboratory test 
results, and study product inventory records) will be retained until the subject is 23 years of age. 
Records will not be destroyed without the permission of the University of Pittsburgh and DMID.  
Informed consent forms for future use will be maintained as long as the sample exists. 
15.5 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP 
requirements. The noncompliance may be either on the part of the subject, the investigators, or 
their study personnel. As a result of deviations, corrective actions will be developed 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 participating clinical study site to use continuous vigilance to identify 
and report deviations within five working days of identification of the protocol deviation, or within 
five working days of the scheduled protocol-required activity. All deviations will be reported to 
the University of Pittsburgh, DMID and DSMB. Protocol deviations must also be reported to the 
local IRBs per their guidelines. The investigators and their study personnel are responsible for 
knowing and adhering to their IRB requirements. 
All deviations from the protocol will be addressed in study subject source documents. A 
completed copy of the Protocol Deviation Form will be maintained in the regulatory file, as well 
as in the subject’s source document. 

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16 
PUBLICATION POLICY 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic version 
of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly 
available no later than 12 months after the official date of publication. The NIH Public Access 
Policy ensures the public has access to the published results of NIH funded research. It requires 
investigators to submit final peer-reviewed journal manuscripts that arise from NIH funds to the 
digital archive PubMed Central upon acceptance for publication. Further, the policy stipulates 
that these papers must be accessible to the public on PubMed Central no later than 12 months 
after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH OER Grants and Funding, http://grants.nih.gov/grants/oer.htm 
Following completion of this clinical trial, the lead principal 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* (http://clinicaltrials.gov/), which is sponsored by the National Library of 
Medicine. Other biomedical journals are considering adopting similar policies. 
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. 
For trials in which DMID is not the IND/IDE sponsor, or there is no IND/IDE, and DMID does not 
provide data management services, it is the responsibility of the investigator to register the trial 
and post results in compliance with Public Law 110-85, the Food and Drug Administration 
Amendments Act of 2007 (FDAAA). 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. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
*Journal Citation:  De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. 
Clinical trial registration: a statement from the International Committee of Medical Journal 
Editors. N Engl J Med. 2004; 351:1250-1. 

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17 
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Wald ER, Applegate KE, Bordley C, et al. Clinical practice guideline for the diagnosis 
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Young J, De Sutter A, Merenstein D, et al. Antibiotics for adults with clinically diagnosed 
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McQuillan L, Crane LA, Kempe A. Diagnosis and Management of Acute Sinusitis by 
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37. 
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Hoberman A, Dagan R, Leibovitz E, et al. Large dosage amoxicillin/clavulanate, 
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DeByle C, Bulkow L, Miernyk K, et al. Comparison of nasopharyngeal flocked swabs and 
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Munywoki PK, Hamid F, Mutunga M, Welch S, Cane P, Nokes DJ. Improved Detection 
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BMC Med Res Methodol. 2012;12:185. 
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67. 
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68. 
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69. 
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Biometrika. Dec 1986;73(3):751-754. 
 

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18 
SUPPLEMENTS 
18.1 Supplement A: Schedule of Events 
  
 
Study Procedure 
Screening/ 
Enrollment/ 
Baseline/Entry 
Visit 
(Day 1) 
Follow-up 
eVisits 
(Days 
2-11*) 
Unscheduled/ 
Interim 
(Sick) 
Visit 
Final End-of-
Study 
Follow-up 
Visit 
(Days 12-18) 
Informed Consent 
X 
 
 
 
Randomization 
X 
 
 
 
Study Product Administration 
X 
X 
 
 
Medical History 
X 
 
X 
X 
Assessment of Face/Nose 
X 
 
X 
 
PRSS Score 
X 
X 
X 
X 
Nasopharyngeal Swab (or 
Mid-Turbinate) obtained 
when possible 
X 
 
 
X 
Adherence Assessment 
 
X 
 
 
Concomitant Medications 
X 
 
X 
X 
Monitoring of Adverse 
Events 
X 
X 
X 
X 
Collect Unused Study 
Product 
 
 
 
X 
*Data collected using an electronic diary. Parents/legal guardians of subjects with missing diaries will be called. 
 
 

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18.2 Supplement B: Pediatric Rhinosinusitis Symptom Scale (PRSS) 
         
How has your child been doing? 
 
We are interested in finding out how your child has been doing over the last 24 hours. Please 
answer these questions with the help of your child. For each question, please place a check (ü) 
in the box corresponding to your child’s symptoms. Please answer all questions.  
Did your child… 
© University of Pittsburgh, 2015 
 
Thank you 
 
 
 
No 
Almost 
None 
A Little 
Some 
A Lot 
An 
Extreme 
Amount 
Have a stuffy nose 
today? 
r 
r 
r 
r 
r 
r 
Have a runny nose 
today? 
r 
r 
r 
r 
r 
r 
Cough during the day? 
r 
r 
r 
r 
r 
r 
Act more tired than 
usual today? 
r 
r 
r 
r 
r 
r 
Act irritable or fussy 
today? 
r 
r 
r 
r 
r 
r 
Have trouble breathing 
through the nose today? 
r 
r 
r 
r 
r 
r 
Cough last night? 
r 
r 
r 
r 
r 
r 
Have trouble sleeping 
last night? 
r 
r 
r 
r 
r 
r