Clinical trial NCT02567825
Conditions: Acute Otitis Media
Keywords: ear infection antibiotics infants children pediatrics tympanostomy tubes
Sponsor: Alejandro Hoberman
Start date: 2015-11-01; Completion date: 2021-02-01
Enrollment: 250 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine whether tympanostomy tube placement (TTP) compared with nonsurgical management will meaningfully improve children's acute otitis media (AOM) experience over the succeeding 2 years.

Detailed description:
Tympanostomy tube placement (TTP) for recurrent acute otitis media (rAOM) is frequently performed in children under 3 years of age; however, a critical need exists to establish its risk/benefit ratio. Seventy percent of children experience at least one episode of AOM during the first year of life; 20% of children have rAOM. The efficacy of TTP for preventing rAOM, assumedly by maintaining middle-ear ventilation, remains unclear. Benefits of TTP must be balanced against risks of anesthesia, complications and sequelae of surgery, and cost. Accordingly, the objective of this proposal is to determine the efficacy of TTP in children aged 6-35 months, the group in which rAOM is most troublesome. The central hypothesis is that in children with rAOM, the operation will prove effective over the ensuing 2 years overall, but the benefit in a more severely affected, and therefore higher-risk subgroup may be substantially greater than in a less severely affected subgroup, in whom benefits may not outweigh risks. The rationale for this research is based on a belief that the limited nature of the benefit of TTP found in earlier clinical trials may have been the result of enrolling children whose illnesses had not been diagnosed using stringent criteria and/or whose ascertainment of episodes had relied on undocumented histories. The primary objective is to determine the extent to which TTP reduces the overall rate of recurrences in children with rAOM over a 2-year period. In a randomized, clinical trial, children aged 6-35 months who are at risk for rAOM will be followed prospectively and examined promptly with new respiratory illnesses to accurately document episodes of AOM. A total of 240 children who meet stringent inclusion criteria for rAOM will be eligible to undergo randomization within strata (age and exposure to other children) to receive TTP or nonsurgical management. Children will be followed for 2 years; the average number of episodes of AOM will be documented and compared between groups. The secondary objective is to determine changes following TTP in nasopharyngeal (NP) colonization with resistant bacteria. At the time of randomization and 3 times a year for 2 years, NP specimens will be obtained and cultured. Susceptibility testing and serotyping will be performed, and the proportions of children colonized with resistant bacteria compared between treatment groups. The tertiary objective is to determine cost-effectiveness of TTP. The investigators will calculate both direct medical and nonmedical costs and correlate this with the number of days that each child has AOM symptoms, otorrhea, and any adverse events or complications. The proposed research is innovative, as the investigators will document AOM episodes prospectively using stringent diagnostic criteria and obtain digital tympanic membrane images otoendoscopically to enhance accuracy of observations. Findings of the proposed study will provide clinicians and parents with dependable evidence concerning the overall effects of TTP compared with nonsurgical management in children with rAOM of varying degrees of severity, enabling evidence-based decisions regarding an important component of the children's healthcare.

Arms: arm 1: Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops arm 2: Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone
Interventions: intervention 1: Tympanostomy tube placement intervention 2: Amoxicillin-Clavulanate and/or Ceftriaxone intervention 3: Ofloxacin Otic
Intervention descriptions: intervention 1: As per routine care, tympanostomy tubes will be inserted under general anesthesia, using a small radial incision in the anteroinferior portion of the tympanic membrane; a Teflon® Armstrong-type tympanostomy tube will be used. intervention 2: Children randomized to nonsurgical management will receive stepwise therapy with amoxicillin-clavulanate (90/6.4 mg/kg in two divided doses for 10 days), and in the event of inadequate response, ceftriaxone (75 mg/kg intramuscularly, repeated in 48 hours), as recommended in the American Academy of Pediatrics guidelines. intervention 3: Participants randomized to receive tympanostomy tubes will also be followed overtime for recurrences of AOM and treated with topical ofloxacin (Floxin® 0.3%, 5 mL) 5 drops into the affected ear twice daily for 10 days. Persistence of otorrhea after 7 days of treatment will be considered inadequate response, and children so affected will be prescribed empiric amoxicillin-clavulanate (90/6.4 mg/kg/day in two divided doses) followed by culture-directed therapy 48 hours later.

Protocol documents:
Prot_SAP_002.pdf: 
NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
1 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media 
NIDCD Protocol Number: 1U01DC013995-01A1 
 
Pharmaceutical Support Provided by: Not Applicable 
Other Identifying Numbers: Not Applicable 
IND Sponsor: Not Applicable 
Principal Investigator: Alejandro Hoberman, MD 
Draft or Version Number: Version 3.0 
August 13, 2018 
NCT02567825 
 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
2 
STATEMENT OF COMPLIANCE 
This study 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 56, and 21 CFR Part 312) 
• International Conference on Harmonization (ICH) E6; 62 Federal Register 25691 (1997) 
• National Institutes of Health (NIH) Clinical Terms of Award 
• Approved protocol 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
3 
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. 
 
 
Signed:  _______________________      Date: _______________ 
Name: Alejandro Hoberman, MD 
 
Signed:  _______________________      Date: _______________ 
Name: Diego Preciado, MD, PhD 
 
Signed:  _______________________      Date: _______________ 
Name: Stanley Block, MD 
 
 
 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
4 
TABLE OF CONTENTS 
 
Page 
Statement of Compliance 
2 
Signature Page 
3 
Table of Contents 
4 
List of Abbreviations 
7 
1 
Key Roles 
9 
2 
Background Information and Scientific Rationale 
11 
2.1 
Background Information............................................................................................11 
2.2 
Rationale ...................................................................................................................17 
2.3 
Potential Risks and Benefits .....................................................................................17 
2.3.1 Potential Risks ..............................................................................................17                  
2.3.2 Adequacy of Protection Against Risk ...........................................................18 
2.3.3    Potential Benefits ……………………………………………………………….19 
                     2.3.4    Importance of the knowledge to be gained ………………………………….19 
3 
Objectives 
21 
3.1 
Study Objectives .......................................................................................................21 
3.2 
Study Endpoints ........................................................................................................22 
3.2.1 Primary Endpoint ..........................................................................................22 
3.2.2 Secondary Endpoints ....................................................................................24 
4 
Study Design 
27 
5 
Study Enrollment and Withdrawal 
31 
5.1 
Eligibility Criteria........................................................................................................31 
5.2 
Subject Exclusion Criteria .........................................................................................32 
5.3 
Treatment Assignment Procedures ..........................................................................32 
5.3.1 Randomization Procedures ..........................................................................32 
5.3.2 Masking Procedures .....................................................................................32 
5.3.3 Reasons for Withdrawal................................................................................33 
5.3.4 Handling of Withdrawals ...............................................................................33 
5.3.5 Termination of Study .....................................................................................33 
6 
Study Intervention/Investigational Product 
34 
7 
Study Schedule 
35 
7.1 
Screening ..................................................................................................................34 
 
7.1.1 Screening Phase - Enrollment - Visit 
35 
 
7.1.2 Screening Phase Sick Visit 
36 
7.2 
Randomization Phase and Treatment Assignment..................................................36 
 
7.2.1 Randomization Phase Follow-up Every 8 Weeks 
37 
 
7.2.2 Randomization Phase Sick Visit 
39 
         7.3       End of Study Visit ……………………………………………………………………….40                         
8 
Study Procedures/Evaluations 
43 
8.1 
Clinical Evaluations ...................................................................................................43 
8.2 
Concomitant Medications/Treatments ......................................................................44 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
5 
8.3 
Special Procedures………………………………………………………………………43 
8.4 
Clinical Laboratory Evaluations ................................................................................45 
8.4.1 Specimen Preparation, Handling, and Shipping ..........................................47 
9 
Assessment of Safety 
48 
9.1 
Specification of Safety Parameters ..........................................................................48 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety       
Parameters................................................................................................................48 
9.2.1 Adverse Events .............................................................................................48 
9.2.2 Reactogenicity...............................................................................................49 
9.2.3 Serious Adverse Events ...............................................................................49 
9.2.4 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings...........................................................50 
9.3 
Reporting Procedures ...............................................................................................50 
9.3.1 Serious Adverse Events ...............................................................................51 
9.3.2 Reporting of Pregnancy ................................................................................51 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events .........................52 
9.5 
Halting Rules .............................................................................................................52 
9.6 
Safety Oversight (ISM plus DSMB) ..........................................................................52 
10 
Clinical Monitoring 
55 
10.1 
Site Monitoring Plan ..................................................................................................55 
11 
Statistical Considerations 
56 
11.1 
Introduction ...............................................................................................................56 
11.2 
Objectives .................................................................................................................56 
11.3 
Study Design .............................................................................................................56 
11.4 
Analysis Populations .................................................................................................57 
 
11.4.1 Intent-to-Treat Population (ITT) 
57 
 
11.5 
Study Assessments 
 
 
11.5.1 Baseline Assessments 
57 
 
 
11.5.2 Efficacy Assessments 
57 
 
 
 
11.5.2.1 
Primary Efficacy Variable 
57 
 
 
 
11.5.2.2 
Secondary Efficacy Variables 
57 
 
 
11.5.3 Safety and Tolerability Assessments 
58 
 
11.6 
Statistical Analysis 
59 
 
 
11.6.1 General Considerations 
59 
 
 
11.6.2 Interim Analysis 
59 
 
 
11.6.3 Subject Disposition 
60 
 
 
11.6.4 Baseline (Pre-Treatment) Analyses 
60 
 
 
11.6.5 Medication Use 
60 
 
 
11.6.6 Efficacy Analyses 
60 
 
 
 
11.6.6.1 
Primary Efficacy Analysis of the Primary Efficacy Endpoint 
60 
 
 
 
11.6.6.2 
Secondary Efficacy Analyses 
61 
 
 
 
11.6.6.3 
Statistical Analysis for Specific Aim 1 
61 
 
 
 
11.6.6.4 
Statistical Analysis for Specific Aim 2 
62 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
6 
 
 
 
11.6.6.5 
Statistical Analysis for Specific Aim 3 
62 
 
 
 
11.6.6.6 
Missing Data 
63 
 
 
 
11.6.6.7 
Handling of Withdrawal/Cross-Overs 
63 
 
 
11.6.7 Safety and Tolerability Analyses 
64 
 
 
 
11.6.7.1 
Adverse Events 
64 
 
 
 
11.6.7.2 
Resource Utilization 
65 
 
 
11.6.8 Sample Size Justification 
66 
12 
Source Documents and Access to Source Data/Documents 
67 
13 
Ethics/Protection of Human Subjects 
68 
13.1 
Ethical Standard........................................................................................................68 
13.2 
Institutional Review Board ........................................................................................68 
13.3 
Informed Consent Process .......................................................................................68 
13.3.1 Informed Consent/Assent Process (in Case of a Minor)..............................69 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) .....................69 
13.5 
Subject Confidentiality ..............................................................................................69 
13.6 
Costs, Subject Compensation, Research Related Injuries ......................................72 
13.7 
Study Discontinuation ...............................................................................................72 
13.8 
Future Use of Stored Specimens .............................................................................72 
14 
Data Handling and Record Keeping 
73 
14.1 
Data Management Responsibilities ..........................................................................73 
14.2 
Data Capture Methods..............................................................................................74 
14.3 
Types of Data ............................................................................................................74 
14.4 
Timing/Reports ..........................................................................................................75 
14.5 
Study Records Retention ..........................................................................................75 
14.6 
Protocol Deviations ...................................................................................................75 
15 
Publication Policy 
77 
16 
Literature References 
78 
Supplements/Appendices 
84 
Appendix A: Schedule of Events 
85 
Appendix B: AOM-SOS Scale 
86 
 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
7 
LIST OF ABBREVIATIONS 
AAP 
American Academy of Pediatrics 
AE 
Adverse Event 
AOM  
Acute Otitis Media 
AOM-SOS  
Acute Otitis Media-Severity of Symptoms Scale 
CCP 
Children’s Community Pediatrics 
CFR  
Code of Federal Regulations 
CHP of UPMC 
Children’s Hospital of Pittsburgh of University of Pittsburgh 
Medical Center 
CIQ 
CNMC 
CO2 
Caregiver Impact Questionnaire 
Children’s National Medical Center 
Carbon Dioxide 
CRA 
Clinical Research Associate 
CRNP  
Certified Registered Nurse Practitioner 
DCC 
Data Coordinating Center 
DHHS  
Department of Health and Human Services 
DMSU 
DSMB  
Data Management and Statistical Unit 
Data and Safety Monitoring Board 
DxEAR 
Diagnostic Ear Assessment Resource 
eCRF 
Electronic Case Report Form 
ENT 
ePROM 
Ear Nose and Throat 
Enhancing Proficiency in Otitis Media 
FDA  
Food and Drug Administration 
FDAAA 
GCP  
Food and Drug Administration Amendments Act of 2007 
Good Clinical Practice 
H. influenzae 
Haemophilus influenzae 
ICH  
International Conference on Harmonization 
IRB  
Institutional Review Board  
ISM  
Independent Safety Monitor 
ITT 
Intent-to-treat 
M. catarrhalis 
Moraxella catarrhalis 
MIC  
Minimum Inhibitory Concentration 
Micro Lab 
MOP 
Microbiology Laboratory 
Manual of Procedures 
N  
Number (typically refers to subjects) 
NCCLS  
National Committee for Clinical Laboratory Standards 
NIAID  
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH  
National Institutes of Health 
NLM 
NP  
National Library of Medicine 
Nasopharyngeal 
OM-6 
OME  
Otitis Media 6 Questionnaire 
Otitis Media with Effusion 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
8 
PA  
Pennsylvania 
PCV-7 
PCV-13 
Pneumococcal Conjugate 7-valent vaccine 
Pneumococcal Conjugate 13-valent vaccine 
PDD 
PE  
Protocol Defined Diarrhea 
Physical Examination 
PittNet PBRN 
Pediatric Practice Based Research Network 
RN  
Registered Nurse 
S. pneumoniae 
Streptococcus pneumoniae 
SAE  
Serious Adverse Event 
SOP  
SOS 
Standard Operating Procedure 
Severity of Symptoms 
TT 
TTP 
TBD  
Tympanostomy Tubes 
Tympanostomy Tube Placement 
To Be Determined 
TM 
Tympanic Membrane 
US 
 
United States 
 
 
 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
9 
1 
KEY ROLES 
For questions regarding this protocol, contact: Robin M. Mason, Program Officer, Respiratory 
Diseases Branch, NIDCD/NIAID, (301) 451-3746, rmason@niaid.nih.gov. 
Individuals: 
 
 
NIDCD Scientific Lead/  
Medical Officer: 
 
Steven Hirschfeld, MD PhD 
Captain, USPHS 
Associate Director for Clinical Research 
Eunice Kennedy Shriver National Institute of Child Health and 
Human Development 
Chief Medical Officer 
Rapid Deployment Force PHS-1 
 
Bracie Watson 
Division of Scientific Programs 
Bldg. NSC, Rm 8305 
Mail Stop 9670 
 
NIDCD Clinical Project Manager: 
NIDCD Medical Monitor: 
Principal Investigators: 
Alejandro Hoberman, MD 
Professor of Pediatrics 
University of Pittsburgh School of Medicine  
Chief, Division of General Academic Pediatrics  
CHP of UPMC 
General Academic Pediatrics, CHOB 3rd Floor  
4401 Penn Avenue; Pittsburgh, PA 15224 
412-692-5249  
412-692-5807 fax  
hoberman@chp.edu 
 
 
Diego Preciado, MD, PhD 
Associate Professor of Otolaryngology, Pediatrics and 
Integrative System Biology 
The George Washington University School of Medicine 
Fellowship Program Director 
Division of Pediatric Otolaryngology 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
10 
Children’s National Medical Center 
111 Michigan Ave., NW 
Washington, DC 20010 
202-423-5535 
202-476-5038 fax 
dpreciad@cnmc.org 
 
Stanley L. Block, MD, F.A.A.P. 
KPAR 
Kentucky Pediatric/Adult Research 
201 S Fifth St 
Bardstown, KY 40004 
 
 
Institutions: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CHP of UPMC 
4401 Penn Avenue 
Pittsburgh, PA 15224 
 
University of Pittsburgh 
Graduate School of Public Health 
Department of Biostatistics 
309B Parran Hall 
130 DeSoto St 
Pittsburgh, PA 15261 
 
Children’s National Medical Center 
111 Michigan Ave., NW 
Washington, DC 2001 
 
KPAR 
201 S Fifth St 
Bardstown, KY 40004 
 
 
 
 
 
Please refer to the protocol-specific communication plan in the 
Manual of Procedures (MOP) for other contact information. 
 
 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
11 
2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
In 2006, the most recent year for which data are available, 667,000 US children under age 15 
years underwent tympanostomy tube placement (TTP) for otitis media, making it the most 
frequently performed surgical procedure after the newborn period in this age group, and 
constituting more than 20% of all ambulatory surgeries in this age group.1 Most of the operations 
were performed in children under 3 years of age.  
Seventy percent of children experience at least one episode of acute otitis media (AOM) during 
the first year of life,2,3 and 93% by age 7.4 About 20% have recurrent AOM (rAOM), conventionally 
defined as ≥3 episodes in 6 months or ≥4 episodes in 12 months with at least 1 episode in the 
preceding 6 months. Efforts to reduce the rate of recurrence in such children have embodied two 
main approaches: low-dose antimicrobial prophylaxis or TTP. Studies of the efficacy of these 
approaches have been relatively few and have had various methodological limitations, particularly 
regarding ascertainment of previous AOM episodes and the stringency of criteria used for the 
diagnosis of AOM and for clinical trial eligibility. In these studies, prophylaxis has appeared 
effective in reducing by about half the number of AOM episodes in the succeeding 2 years, 
amounting to a reduction of about 0.5 to 1.5 episodes per child-year.5 However, prophylaxis 
seems no longer advisable because of concerns about its adverse effects and its contribution to 
the emergence of bacterial resistance.6 The efficacy of TTP for preventing rAOM, assumedly by 
maintaining middle-ear ventilation, remains unclear; limited evidence suggests short-term 
benefits similar in magnitude to those of antimicrobial prophylaxis.7 An advantage of TTP is that 
AOM in children with tubes can be treated with topical rather than systemic antibiotics, potentially 
minimizing adverse effects and contributions to bacterial resistance. Benefits of TTP, however, 
must be balanced against (1) risks of anesthesia, especially before age 3 years,8 and of the 
development, after surgery, of tube otorrhea, blockage of the tube or its premature extrusion or 
displacement into the middle ear cavity, and tympanic membrane (TM) scarring, retraction pocket, 
granulation tissue, or persistent perforation;9 and (2) cost. Although in recent years, there has 
been a noticeable decline in the overall number of TTP procedures,10 it seems plausible that this 
decline may result from a greater decline of TTP procedures among children with persistent 
middle-ear effusion that outweighs an increase in procedures among children with rAOM. A critical 
need thus exists on behalf of such children to establish TTP’s risk/benefit ratio.  
Review of Relevant Literature. The efficacy of TTP in preventing recurrences has been studied in 
four randomized, controlled trials of children referred to ENT because of history of rAOM.11-14 In 
two trials some children also had persistent middle ear effusion (MEE) at entry.11,12 In one of 
these, Gebhart et al. randomized 108 children age <3 years to either TTP or observation, and 
followed them for 6 months. Among the 95 children for whom results were available, 54 children 
in the TTP group had 36 AOM episodes and 41 children in the observation group had 89 episodes 
(rate difference 1.3 vs. 4.3 episodes per child-year; P<0.001).12 In the other trial, Gonzalez et al. 
randomized 63 children aged <4 years to either TTP, prophylaxis, or placebo, and followed them 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
12 
for 6 months. Treatment failure was defined as ≥2 episodes of either AOM or otorrhea within 3 
months. Five of 22 children in the TTP group failed, compared with 12 of 20 in the placebo group 
(P=0.03). During 6 months, 19 AOM episodes occurred among 22 children in the TT group, 
compared with 40 among the 20 children in the placebo group (rate difference 1.7 vs. 4.0 episodes 
per child-year; P<0.01).11 Casselbrant et al. randomized 264 children 7 to 35 months of age free 
of MEE to either prophylaxis, TTP, or placebo, and followed them for 2 years. No significant 
difference was noted between children undergoing TTP and children receiving placebo in the 
average number of AOM episodes (rate difference 1.03 vs. 1.08 episodes per child-year; P=0.25). 
Persistent TM perforations developed in 4% of children in the TTP group.13 Kujala et al. randomly 
assigned 300 children aged 10 months to 2 years to either TTP, TTP plus adenoidectomy, or 
neither, and followed them for 12 months. The primary outcome was intervention failure, defined 
as ≥2 AOM episodes in 2 months, ≥3 in 6 months, or persistent MEE for 2 months. Failure 
occurred in 21 of 100 children in the TTP group (21%), 16 of 100 children in the TTP plus 
adenoidectomy group (16%), and 34 of 100 children in the control group (34%) (rate differences 
−13% [95% CI −25% to −1%] between the TTP group and the control group, P=0.04; and −18% 
[95% CI −30% to −6%] between the TTP plus adenoidectomy group and the control group, 
P<0.01). Reductions in the rate of AOM recurrences provided by surgery were modest: compared 
with the rate of 1.70 episodes per child-year in controls, the rate in children undergoing TTP was 
1.15 (difference −0.55 [95% CI −0.93 to −0.17]), and the rate in children undergoing TTP plus 
adenoidectomy was −0.91 (difference −0.79 [95% CI −1.14 to −0.43]).14 
A recent systematic review of TTP in children with rAOM concluded: “evidence of the effect of… 
insertion of TT is very limited. In light of the relatively small effect it seems ethical to carry out 
well-designed randomized studies with non-treatment control groups and relevant outcome 
measures as improvement in quality of life for children and the whole family, absence from day 
care, parents absent from work, and adverse effects.”7 In the present ear nose and throat (ENT) 
and pediatric practice paradigms, antimicrobial prophylaxis is no longer acceptable because 
assessment of the relative risk-benefit profiles has shifted given short- and long-term effects of 
injudicious antibiotic use.6 Because of the large numbers of young children in the U.S. who 
undergo TTP and the remaining uncertainties concerning the efficacy of TTP, we believe it is 
important to settle questions of benefit vs. risk and cost in definable subgroups of children.  
Preliminary Studies 
Investigator experience with large, long-term, randomized, controlled clinical trials.  
Since the 1970s our research team has conducted large-scale, randomized, controlled trials 
evaluating procedures and treatments commonly used for frequently occurring pediatric 
conditions, and has followed successfully large cohorts of children for extended periods of time. 
These trials have included tonsillectomy for recurrent pharyngitis15,16 adenoidectomy for otitis 
media,17,18 TTP for persistent MEE,19 outpatient vs. inpatient antibiotics for acute 
pyelonephritis,20 influenza vaccine for preventing AOM,21 prophylactic antimicrobials for children 
with vesicoureteral reflux,22 antimicrobials for AOM in children under age 2,23 duration of therapy 
for AOM in children under age 2 (5 days vs. 10 days; in progress), and duration of therapy for 
urinary tract infection (5 days vs. 10 days; in progress). Many of these studies have involved 
multiple centers, and most have been supported by NIH. Particularly pertinent to the present 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
13 
proposal are the trial that evaluated the efficacy of antimicrobials for AOM23 and the ongoing 
trial evaluating duration of therapy for AOM, both with similar follow-up procedures. 
Treatment of AOM in Children Under 2 Years of Age23  
291 children 6 to 23 months of age with AOM diagnosed stringently were randomly assigned to 
receive either amoxicillin–clavulanate or placebo for 10 days. Symptomatic response and 
treatment failure rates were measured. Among children who received amoxicillin–clavulanate, 
35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7; among 
children who received placebo, corresponding values were 28%, 54%, and 74%, respectively 
(P=0.14). For sustained resolution of symptoms, corresponding values were 20%, 41%, and 
67% in the amoxicillin–clavulanate group, compared with 14%, 36%, and 53% in the placebo 
group (P=0.04). Mean symptom scores over 7 days were lower for children in the amoxicillin–
clavulanate group than those in the placebo group (P=0.02). The rate of treatment failure 
(persistence of signs of acute infection) was lower for children treated with amoxicillin–
clavulanate than for those receiving placebo: 4% vs. 23% at or before day 4 or 5 (P<0.001) and 
16% vs. 51% at or before day 10 to 12 (P<0.001). Mastoiditis developed in one child who 
received placebo. Diarrhea and diaper dermatitis were more common among children who 
received amoxicillin–clavulanate. No significant changes in rates of nasopharyngeal (NP) 
colonization with nonsusceptible S. pneumoniae were noted.  
Duration of Therapy for AOM in Children Under 2 Years of Age 
We received a contract from NIAID (HHSN272201000047C) to study shortening the duration of 
therapy in young children with AOM as a strategy for reducing the likelihood of antimicrobial 
resistance. This is a Phase 2b multicenter, randomized, double-blind, placebo-controlled clinical 
trial comparing reduced-duration with standard-duration therapy in children aged 6 to 23 months 
with AOM. The trial will compare the efficacy of reduced-duration with standard-duration therapy 
for as many as three successive episodes of AOM, using for each child for each episode a 
consistent strategy entailing the same blinded therapy as assigned at entry. In the event that a 
child develops three episodes, [the third and] any subsequent episodes will be treated with 
amoxicillin-clavulanate for 10 days. Each child will be followed for an entire respiratory season 
(October through May). Final assessment for NP bacterial resistance will occur the following 
September (up to 1-year follow-up). The primary objective is to determine whether reduced-
duration therapy (5 days of amoxicillin-clavulanate + 5 days of placebo) is non-inferior in 
efficacy to standard-duration therapy (10 days of amoxicillin-clavulanate) as determined by the 
proportion of children categorized as treatment failure by Day 12-14. Secondary objectives 
include determining whether a strategy of reduced-duration therapy results in decreased NP 
resistance, no increase in the number of recurrences, decreased antibiotic utilization, no 
increase in symptom burden (Days 6-14), equivalent treatment failure rates during recurrences, 
and an improved safety profile. Exploratory objectives will determine whether the reduced-
duration therapy strategy results in no difference in utilization of healthcare resources and 
increased parental satisfaction with therapy. A total of 520 children were enrolled and will have 
completed follow-up by September 2015. Results are currently being analyzed. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
14 
Investigator contributions toward enhancing AOM diagnostic accuracy and increasing the 
stringency of AOM diagnostic criteria, and investigator efforts to increase precision of research 
outcomes 
Drs. Hoberman, Paradise and Shaikh have devoted continuing effort to improving methods of 
teaching physicians accurate diagnosis of otitis media, particularly differentiating AOM from 
otitis media with effusion (OME), through publications23-26 and images obtained 
otoendoscopically. These programs have been presented at meetings of the Pediatric Academic 
Societies and the American Academy of Pediatrics (AAP), have been used at investigators’ 
meetings for validating the skill of clinicians participating in research, and have been reviewed in 
journals.27,28 We have also developed two Videos in Clinical Medicine for the N Eng J Med, on 
pneumatic otoscopy and cerumen removal, and on diagnostic tympanocentesis.29  
Sponsored by the Centers for Disease Control and Prevention and the Association of American 
Medical Colleges, we developed a comprehensive educational curriculum for training in the 
diagnosis of AOM, which was implemented at 5 residency programs (http://pedsed.pitt.edu; 
ePROM, Enhancing Proficiency in the Diagnosis of Otitis Media).30 At the 2009 Annual meeting 
of the Pediatric Academic Societies, Dr. Hoberman, as Chief of the Division of General 
Academic Pediatrics at Children’s Hospital of Pittsburgh of UPMC (CHP of UPMC) received the 
Outstanding Teaching Award of the Academic Pediatric Association for the development of 
these educational programs. Dr. Hoberman served as a member of the AOM Management 
Guideline Subcommittee of the AAP and was responsible for the diagnostic section that 
endorsed the stringent criteria used in our recent trials.5,23   
To enhance the quality of observations in AOM clinical trials, Dr. Hoberman incorporated the 
diagnostic criteria previously described, together with TM images obtained otoendoscopically, 
into an electronic case report form (eCRF). Investigators complete this form and submit it to a 
central database, triggering an email that has permitted central review of all images obtained in 
recent multicenter AOM clinical trials we have conducted. This technology, recently endorsed in 
a Food and Drug Admnistration (FDA) guidance document for AOM clinical trials, has enabled 
clinicians at participating study sites to discuss otoscopic findings as needed with Dr. 
Hoberman, further enhancing the accuracy of AOM diagnoses that determine eligibility and 
primary outcome. 
Development of rAOM severity/risk scale (rAOM-SRS) 
Using previously reported demographic and clinical characteristics associated with increased 
likelihood of AOM recurrences, Drs. Hoberman and Paradise developed the rAOM-SRS to 
categorize children as either high-risk or low-risk. These categories will be used in secondary 
analyses of treatment efficacy. We assigned ratings of 0, 1, or 2 (shown in parentheses in Table 
1) to each characteristic, based on previously reported strengths of associations and/or our 
clinical experiences. These clinical and demographic factors are operative singly or together 
throughout the child’s prior history including the screening phase of the trial, at the time of 
randomization, and throughout the follow-up period. The factors comprise: (1) early age of onset 
of AOM;3,31 (2) number and frequency of previous episodes of AOM;32 (3) receipt of many 
courses of antibiotics and accordingly at higher risk of developing AOM caused by resistant 
pathogens;33 (4) eligibility for randomization first having become evident during warm-weather 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
15 
months, implying greater likelihood of being otitis-prone;32 (5) overall parental assessment of the 
severity of previous episodes of AOM;31 (6) eligibility for randomization despite not having been 
exposed to other young children;2,23 (7) extreme TM bulging with previous AOM episodes;23 (8) 
usual bilaterality of previous AOM episodes;3,23 and (9) severity of symptoms.23 Five of nine 
scale items relate to increased risk for rAOM; 4 items relate to average severity of recurrences. 
Exposure to other young children subsequent to randomization represents a particularly 
important risk factor; accordingly, we have included it as an independent stratification variable 
rather than in the composite rating. We obtained preliminary data on applying the score to 236 
children enrolled in our duration-of-treatment study described previously (not the previously 
described amoxicillin-clavulanate vs. placebo study whose data contributed to our choice of 
characteristics of interest for the scale) in order to determine whether sufficient numbers of 
children would have been assigned to “high-risk” and “low-risk” groups to permit meaningful 
analyses. The only variable that retrospectively could not be assessed was #5, parental overall 
assessment of previous AOM episodes, due to concerns about recall bias. Accordingly, a total 
of 14 points could potentially be assigned (instead of 16) for the remaining 8 items. A total of 69 
children met criteria for rAOM during their follow-up for one respiratory season (range 60-240 
days); 55% had a total score ≥7 and 35% a score ≥8. The Figure shows the proportions of 
children in relation to rAOM-SRS scores for 69 children with rAOM and 167 children who had 
AOM but did not meet rAOM criteria during one respiratory season. Consistently among children 
with rAOM-SRS scores ≥7, the percentages of rAOM children were greater than the 
corresponding percentages of non-rAOM children, with the reverse being the case for children 
with scores ≤ 6. The mean scores were 6.49 [2.26] vs. 5.54 [2.15] for rAOM and non-rAOM 
groups, respectively; P=0.003).  
 
 
 
 
 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
16 
Antimicrobial resistance trends in children with AOM 
We have conducted studies of children with AOM for over 15 years, following trends in 
antimicrobial resistance and Streptococcus pneumoniae serotype prevalence as well as findings 
concerning other pathogens.21,23,34-36 In studies conducted before the introduction of 7-valent 
pneumococcal conjugate vaccine (PCV7), and up to and including the period following the 
introduction of 13-valent pneumococcal conjugate vaccine (PCV13), we reported that despite 
community-wide efforts to decrease inappropriate use of antibiotics, the relatively high 
prevalence in this community of S. pneumoniae isolates that are penicillin-nonsusceptible has 
remained essentially unchanged. We have observed considerable change in serotypes of S. 
pneumoniae recovered from children with AOM. Before routine vaccination in 1999-2000, 
serotypes observed were principally (59%) those included in PCV7; 25.5% were penicillin-
nonsusceptible. By the mid-2000s, these serotypes had decreased in frequency while new 
serotypes, particularly 19A, emerged. In 2010, when PCV13 was introduced, carriage of PCV7 
serotypes had been virtually eliminated (1.8%), and 19A had decreased substantially and been 
replaced by new serotypes. Predominant serotypes observed have been 15A/B/C (23.3%)--30% 
penicillin-nonsusceptible, followed by 35B (8.9%)--100% penicillin-nonsusceptible. The 
prevalence of levofloxacin resistance among S. pneumoniae isolates has been 1%. Table 3 
below summarizes serotype distribution and susceptibility information from our previous and 
ongoing clinical trials, and illustrates the virtual disappearance of PCV7 serotypes, the 
subsequent decrease in PCV13 serotypes, and the more recent emergence of non-vaccine 
serotypes. Other studies have had similar findings.37-40  
Our studies 
since 1999 
showed that NP 
colonization 
with 
Haemophilus. 
influenzae had 
an initial 
increase (41%) 
in 2003-2005 
suggesting 
replacement of 
S. pneumoniae 
after 
introduction of PCV7; however, this was followed by a decrease in colonization in our most 
recent cohort (2012-2014). Currently, 29% of children 6-23 months of age with AOM are 
colonized with H. influenzae.41 Further, our recent data on 206 children support the findings that 
children with infrequent episodes of AOM and less systemic antibiotic exposure (n=146) are 
less likely to be colonized with resistant bacteria (7.5% non-susceptible S. pneumoniae or ß-
lactamase + H. influenzae) than otitis-prone children (n=60)(18.3%; P=0.04). Accordingly, we 
expect that children randomized to TTP will be exposed to less systemic antibiotic and will be 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
17 
less likely to be colonized with resistant pathogens. These findings indicate continuing change 
and underscore the need for vigilance to inform vaccine development and clinical management. 
Investigator experience in establishing collaboration with otolaryngologists in the design and 
implementation of various studies, including particularly clinical trials involving surgical vs. 
nonsurgical management; consistent, high-quality statistical support; and experience in 
communicating with and obtaining informed consent from families in order to obtain participation 
of their children in trials addressing treatments or procedures for which equipoise exists 
Since the late 1960s we have developed cooperative working relationships in planning and 
executing large clinical studies in collaboration with otolaryngologists.9,16-19,42-44, These studies 
have included various clinical trials in which children were randomized to receive or not receive 
a specific surgical procedure (i.e. tonsillectomy, adenoidectomy, or TTP). All of these studies 
over the past 22 years have benefited from key participation in planning and co-responsibility for 
analysis by a single statistical team comprising Howard Rockette, PhD, Marcia Kurs-Lasky, MS, 
and more recently Jong-Hyeon Jeong, PhD, all of whom have particular expertise in analyzing 
specific outcomes in clinical trials. We have also recently studied reasons for parents’ 
consenting or not consenting to allow their children to participate in clinical research studies.45 In 
recognition for his research accomplishments, Dr. Hoberman received the Academic Pediatric 
Association 2014 Research Award. The award acknowledges the contribution of an individual in 
advancing pediatric knowledge through excellence in research, characterized by originality, 
creativity and methodological soundness.46 
2.2 
Rationale 
The rationale for this research is based on a belief that the limited nature of the benefit of TTP 
found in earlier clinical trials may have been the result of enrolling children whose previous illness 
episodes had not been diagnosed using stringent criteria and/or whose ascertainment of illness 
had relied on undocumented histories. In contrast, as in our recent clinical trial,23 in our projected 
trial comparing TTP with nonsurgical management, clinicians will be trained otoscopists, all 
observations will be documented and supported with digital TM images obtained 
otoendoscopically (endorsed recently by the U.S. FDA, and we will use stringent AOM diagnostic 
criteria (endorsed recently in AAP guidelines5) coupled with stringent entry criteria and close 
follow-up.  
2.3 
Potential Risks and Benefits 
 
2.3.1 Potential Risks 
TTP carries with it the potential risks of anesthesia, especially before age 3 years, and of the 
development, following surgery, of tube otorrhea, blockage of the tube, or its premature extrusion 
or displacement into the middle ear. Possible TM sequelae include scarring, retraction pocket, 
granulation tissue, and persistent perforation.Finally, the cost of TTP is substantial. By avoiding 
overuse should TTP prove to have limited effectiveness, fewer young children will be exposed to 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
18 
general anesthesia, long-term TM sequelae, and health care expenditures may be lessened. The 
primary risk of participation in the study for children randomized to nonsurgical management 
would be the potential for developing rAOM that would be treated with systemic antimicrobials (as 
opposed to topical antibiotics) with a resulting increase in certain adverse events (principally 
diarrhea and yeast infections), and the potential for encouraging the emergence of bacterial 
resistance. An important potential benefit of this study,should TTP prove to be quite efficacious, 
consists of the possibility that fewer children may develop NP colonization with resistant bacteria, 
with correspondingly fewer day care and adult/elderly household contacts becoming colonized, 
thus reducing the risk of their developing invasive or noninvasive pneumococcal disease. Under 
such conditions, the risk of iimpairment of overall child/family functional might be lessened.  
Parents will be informed of these possibilities, and advised that no definitive standard of care 
exists, particularly in light of the increasing trend toward sharp reductions in the use of prophylactic 
antimicrobials because of concerns about the emergence of bacterial resistance. They will be 
advised in the informed consent document that TTP is widely accepted by physicians in the US, 
but not necessarily in other countries where a lack of consensus exists regarding the advisability 
of TTP for rAOM. As noted below, the investigators will follow study participants closely after 
initiating therapy for an AOM episode, and with follow-up visits scheduled every 8 weeks. We will 
ask parents to bring their children to be examined by our study team if they develop persistent 
respiratory symptoms or within 48 hours after  the development of any symptom suggestive of 
AOM.  
 
2.3.2 Adequacy of protection against risk 
Recruitment and Informed Consent 
All key personnel and research staff have completed the required training and certification for 
research integrity, protection of human subjects, research with children, HIPAA privacy, and 
blood-borne pathogens. Children for this study will be recruited from several pediatric general 
practice locations into a screening phase and will have to meet all inclusion and exclusion criteria 
before actual enrollment into the randomized phase of the study. In the screening phase, we will 
obtain informed consent from the parent(s) of children who are felt to be at risk for rAOM, and 
follow them prospectively. In order to document the occurrence a minimum of one episodes of 
AOM during the screening phase, children will be followed closely and examined by our study 
team. We will ask parents to bring their children to be examined by our study team if they develop 
persistent respiratory symptoms or within 48 hours after the development of any symptom 
suggestive of AOM. This will be required in order for subjects to move to the randomization phase. 
Once the study has been explained, all questions have been answered, and informed consent 
has been obtained, eligible subjects will undergo central randomization within strata based on 
age (6-11 months, 12-23 months and 24-35 months) and degree/history of exposure to other 
children (exposed, or not exposed to ≥3 children for ≥10 hours/week). 
 
Treatment Group A:  TTP 
 
Treatment Group B:  Nonsurgical management 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
19 
Randomization information will be programmed into the eCRF and study personnel will schedule, 
within 2 weeks, TTP for children who are assigned to treatment group A. No attempt will be made 
to blind treatment assignment.  
Protection against risk 
Study investigators will be available through a cellular phone (412) 999-EARS 24 hours a day, 7 
days a week for children enrolled in the study. Parents will be asked about their child’s overall 
clinical status and children will be seen within 48 hours (usually on the same day) or referred to 
the Emergency Department (ED) if deemed appropriate.  
All paper records containing identifying information will be kept in locked files accessible only to 
study staff and unlocked only while a study staff member is working with the files. Information 
regarding individual subjects will be kept private and shared only with the IRB and appropriate 
government agencies. Primary care providers will be informed about their patient’s progress 
periodically and will be notified if problems in management occur as detailed above.   
 
2.3.3 Potential benefits of the proposed research to the subjects and others 
Study subjects may benefit from early detection and appropriate antibiotic treatment (topical or 
systemic) of recurrences of AOM. This investigation will provide indirect benefit to children who 
experience rAOM because analysis of these carefully collected data will be instructive in 
determining whether children with rAOM should generally be treated with TTP.  
 
2.3.4 Importance of the knowledge to be gained 
This contribution is important because it will provide clinicians and parents the necessary 
evidence to determine whether TTP, as compared with nonsurgical management, results in a 
reduction in the number of children’s AOM recurrences over time, and accordingly supports the 
rationale for the most frequently performed surgical procedure in young US children. If TTP proves 
effective and as a result is used more widely, fewer children may exhibit NP colonization with 
resistant bacteria, and correspondingly fewer adult/elderly household contacts may become 
colonized, thus decreasing their risk of developing respiratory disease, and invasive 
pneumococcal disease in particular. On the other hand, should TTP prove not substantially 
effective and reductions in the number of procedures result, fewer young children will be exposed 
to general anesthesia, and fewer will develop short-term complications of TTP and/or long-term 
TM and possibly auditory sequelae. Under those circumstances, health care expenditures would 
be reduced as well. However, irrespective of the surgical-vs-nonsurgical results, their application 
may be expected to result in improved overall child/family functional status. 
The management of children with rAOM has long been controversial. Efforts to reduce the rate 
of recurrence have taken two approaches: antimicrobial prophylaxis and TTP. Studies 
evaluating these approaches have been characterized by methodological limitations, particularly 
in the ascertainment of previous AOM episodes and in the stringency of AOM diagnostic criteria. 
Further, since antimicrobial prophylaxis seems no longer advisable because of concerns about 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
20 
adverse events and about its contribution to the emergence of bacterial resistance, TTP has 
become a frequently used therapeutic option despite the absence of solid evidence supporting 
its widespread use. A properly designed randomized clinical trial, with stringent AOM diagnostic 
criteria, to determine both eligibility and outcome, in which all observations will be documented 
and supported with digital TM images obtained otoendoscopically (as endorsed by the US 
FDA), together with follow-up for a clinically meaningful 2-year period, will enable us to achieve 
the specific aims of this study, and to provide support for, or call into question this frequently 
performed surgical procedure in children. The proposed investigation is designed to overcome 
the limitations of previous studies and to address this important public health question. Risks to 
participants are outweighed by the potential gains to the children enrolled, and to the many 
other children with rAOM. The stringent safeguards built into the proposal for the early detection 
and treatment of clinical failures and recurrences of rAOM will also help protect study 
participants. Such surveillance would likely not be available outside a study setting. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
21 
3 
OBJECTIVES 
3.1 
Study Objectives 
The present proposal is a Phase 3, multicenter, randomized, clinical trial among children aged 
6-35 months with rAOM. Its goal is to determine whether TTP as compared with nonsurgical 
management will meaningfully improve the children’s AOM experience over the succeeding 2 
years. A total of 240 children diagnosed with rAOM will be enrolled at participating clinical study 
sites, namely, CHP of UPMC, Pittsburgh, PA and its affiliated Pediatric PittNet Practice-Based 
Research Network; and Children’s National Medical Center (CNMC), Washington, DC and its 
affiliated Children’s Pediatricians and Associates Practices (CP&A), and KPAR (Kentucky 
Pediatric/Adult Research) in Bardstown, KY,. Participating clinical study sites will enroll 
approximately 100 eligible children per year over a period of 2.5 years; children will be followed 
for a 2-year period. Children recruited from the target population will reflect the community at 
large at each participating site, encompassing urban (CHP and CNMC), suburban, and rural 
(Pediatric PittNet and CNMC-affiliated practices) populations, to enhance the generalizability of 
study findings and encourage the translation of study findings to clinical practice. 
Primary Objective: 
To determine the efficacy of TTP in children aged 6 to 35 months, the age group in whom rAOM 
is most troublesome. This objective is in keeping with our long-term goal of evaluating frequently 
performed pediatric treatments and procedures that entail substantial use of health care 
resources but whose value has not been adequately substantiated.16,17,19,20,23,47-49 Our central 
hypothesis here is that in children with rAOM who have conventional indications for TTP, the 
operation will prove effective in reducing morbidity from AOM over the ensuing 2 years overall, 
but that the benefit in a more severely affected, and therefore higher-risk subgroup may be 
substantially greater than in a less severely affected subgroup, in whom benefits of TTP may not 
outweigh risks. We will test our central hypothesis by pursuing, in children with rAOM, the 
following specific aim 
To determine the extent to which TTP reduces the rate of AOM recurrences over a 2-year 
period. 
 
Hypothesis: TTP will reduce the rate overall. Secondarily, higher-risk children will experience 
greater benefit than those at lower risk who will have fewer recurrences and for whom benefits 
may not outweigh risks.  
Secondary Objectives: 
To determine whether TTP as compared with nonsurgical management results in: 
• 
Reduced antibiotic resistance of nasopharyngeal pathogens 
• 
Greater cost-effectiveness in children at higher-risk for rAOM than in children at lower-
risk. This will include determination of direct medical and non-medical costs, 
determination of effectiveness by tracking days with either AOM symptoms and intact 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
22 
TMs or tube otorrhea, and medication-related adverse events or complications. 
Secondary cost-effectiveness outcomes will determine how TTP for rAOM affects 
functional outcomes as measured by the OM-6 survey questionnaire and the Caregiver 
Impact Questionnaire (CIQ), to be described later.                
• 
A lower proportion of children categorized as having treatment failure (defined below) 
• 
Less severe AOM episodes, using both the AAP definition (severe, indicated by 
moderate or severe otalgia or temperature >39°C)5 and by the Acute Otitis Media-
Severity of Symptoms (AOM-SOS)30 score on Day 1 of AOM recurrences 
• 
A lower frequency of AOM recurrences 
• 
Longer time-to-first AOM recurrence 
• 
A differential proportion of AOM recurrences presenting with, respectively, intact bulging 
TM or tube otorrhea 
• 
Fewer days per year on which subjects receive systemic antimicrobials for AOM 
• 
Lower proportions and duration of selected adverse events during periods of 
antimicrobial therapy for AOM (protocol defined diarrhea [PDD, defined as the 
occurrence of ≥3 watery stools on 1 day or ≥2 watery stools on each of 2 consecutive 
days], diaper rash necessitating administration of topical antifungal therapy, and  
otorrhea) 
The primary endpoint is the average number of AOM episodes during the 2-year follow-up 
period; we will compare mean rates of AOM recurrence between treatment groups. Secondary 
endpoints include the development of antimicrobial resistance among nasopharyngeal 
pathogens; direct medical and non-medical costs, proportion of children categorized as 
treatment failure (defined below), days with either AOM symptoms and intact TM or tube 
otorrhea, medication adverse events/complications, and functional outcomes for cost-
effectiveness analyses; proportions of severe vs. non-severe AOM episodes; days to first AOM 
recurrence; total number of days children received antibiotics; and the occurrence of PDD up to 
Day 16, diaper dermatitis resulting in the prescription of an antifungal cream, and otorrhea. 
3.2 
Study Endpoints 
 
3.2.1  Primary Endpoint 
The primary endpoint is the average number of AOM episodes during the 2-year follow-up 
period. Children enrolled in the study will be evaluated every 8 (±1) weeks and at any time 
parent(s) or legal guardian(s) suspect the occurrence of AOM. If a subject is evaluated at a non-
participating clinical site, parents will be asked to bring the subject to a study site for further 
evaluation. Findings of AOM will be counted as a recurrence if they have persisted or recurred 
≥17 days after start of treatment for a preceding episode, because: (1) new episodes will have 
been treated with an antimicrobial for 10 days, and (2) most AOM episodes occurring ≥7 days 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
23 
after completion of therapy are new infections with different pathogens rather than bacteriologic 
relapses (in one study, 59%, 74%, 86%, and 90% of infections occurring during the 1st, 2nd, 3rd 
and 4th week after therapy, respectively, were new).50 
Treatment failure. Children will be deemed to have experienced treatment failure if they develop 
at any time any of the following: 
a. 2 AOM recurrences within 3 months, 3 AOM recurrences within 6 months, or 4 AOM 
recurrences within 12 months 
b. ≥3 severe AOM recurrences within 12 months, with “severe” defined as showing either: 
1. Moderate or severe otalgia or temperature >39°C 
2. AOM-SOS score >6 on Day 1 
c. Persistent MEE for ≥12 successive months 
d. Otorrhea for ≥45 days cumulatively within a 12-month period 
e. TM perforation for ≥90 days following extrusion of TT 
f. PDD (associated with antimicrobial therapy for AOM) for ≥30 days cumulatively within a 
12-month period, or treatment with intravenous fluids for PDD (associated with 
antimicrobial therapy for AOM) on ≥2 occasions 
g. Performance of TTP in children assigned originally to the nonsurgical treatment group 
h. Hospitalization for any otitis media-related reason, e.g. (1) unplanned admission 
overnight after surgery that was originally planned as ambulatory; (2) mastoiditis; (3) 
persistent otorrhea caused by pathogens resistant to oral antimicrobials; and (4) PDD 
(associated with antimicrobial therapy for AOM) severe enough to require 
hospitalization. 
i. 
Anesthesia reactions, to include laryngospasm, anaphylaxis, or a need for 
cardiopulmonary resuscitation during surgery; 
j. 
Receipt of ≥45 days cumulatively of systemic antimicrobials for AOM within a 12-month 
period 
Secondarily, estimates of the difference in number of AOM episodes during a 2-year period 
between the TTP and nonsurgical groups in the higher-risk and lower-risk children, respectively, 
will be useful in determining whether TTP is more beneficial for the subgroup of children at 
higher risk. The precision of these estimates will depend on the proportion of children assigned 
to the higher-risk subgroup, as well as on the average number of episodes occurring in each 
risk subgroup. 
Treatment of AOM episodes. Otorrhea occurring in children with TT in place will be considered 
indicative of acute infection, and in such instances a specimen of the discharge for standard 
microbiologic assessment will be obtained, when possible from the tube orifice directly. Such 
children will be treated with topical ofloxacin (Floxin® 0.3%, 5 mL) 5 drops into the affected ear 
twice daily for 10 days. Persistence of otorrhea after 7 days of treatment will be considered 
inadequate response, and children so affected will be prescribed empiric amoxicillin-clavulanate 
(90/6.4 mg/kg/day in two divided doses) followed by culture-directed therapy 48 hours later. 
Children randomized to nonsurgical management will receive stepwise therapy with amoxicillin-
clavulanate (90/6.4 mg/kg in two divided doses for 10 days), and in the event of inadequate 
response, ceftriaxone (75 mg/kg intramuscularly, repeated in 48 hours), as recommended in the 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
24 
AAP guidelines.5 
 
3.2.2 Secondary Endpoints 
• 
Secondary endpoints concerning bacterial resistance include (1) proportions of children 
whose NP cultures at randomization are, respectively, either negative for S. pneumoniae and 
H. influenzae, or positive for penicillin-susceptible pathogens, or positive for one or more 
penicillin-nonsusceptible pathogens, who subsequently are found on a follow-up NP culture 
to harbor one or more penicillin-nonsusceptible pathogens; (2) proportion of interim, non-
illness visits at which a penicillin-nonsusceptible pathogen is recovered; and (3) for all AOM 
episodes, the proportions of S. pneumoniae and H. influenzae isolates recovered at a visit 
during April or May (end of the respiratory season) that are penicillin nonsusceptible. To 
enable these analyses we will obtain, at randomization and every 16 weeks thereafter, an NP 
culture in children aged 6 to 23 months and a throat culture in children aged ≥24 months. An 
incidental by-product of these analyses will be information as to whether the S. pneumoniae 
serotypes found are components of PCV13. 
• 
Relative cost-effectiveness in children at higher risk for rAOM as compared with children at 
lower risk will include determination of direct medical and non-medical costs, determination of 
effectiveness by tracking days with either AOM symptoms and intact TMs or tube otorrhea, 
and medication-related adverse events or complications. Secondary cost-effectiveness 
outcomes will determine how TTP for rAOM affects functional outcomes as measured by the 
OM-6 survey questionnaire and the CIQ.  
Determination of direct medical costs. Direct medical costs include costs of visits to 
healthcare providers and cost of medications, and will be ascertained from parent reports 
and medical records. At study visits every 8 weeks, we will ask parents about number/type 
of encounters with healthcare providers (ED, hospitalizations, surgeries, ENT, primary care 
provider) and about antibiotic use. Cost of research-only visits will not be included, except 
when parents state that it prevented a visit for an AOM-related concern. We will also review 
medical records to ensure that all visits have been captured. We will separate costs into 
those related and unrelated to AOM and its treatment. A clinician, masked to treatment 
assignment, will make this determination. This will allow us to compare both overall costs 
and costs specific to AOM between the two treatment groups.  
We will use a social approach to measuring direct medical costs, and use information on the 
Medicare relative-value physician fee system from the Center for Medicare and Medicaid 
Services database to assign costs to physician services. We will take into account 
information from study records and medical records to assign a Healthcare Common 
Procedure Coding System (HCPCS) code to each visit. For primary care and ED visits, we 
will assume a level-3 service (HCPCS codes 99213 and 99283, respectively), and willl use 
the HCPCS code (69436) to calculate cost of TTP—including a routine postoperative visit to 
the surgeon at 1 month. For the 12-month follow-up visit with the surgeon we will use the 
HCPCS code (99213). The number of visits will be multiplied by the unit cost of each visit. 
We will estimate costs of hospitalizations and ED visits by dividing charges for those visits 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
25 
by the hospital’s cost-to-charge ratio. The number of courses of medications used will be 
multiplied by the unit cost of each medication using the Red BookTM Drug reference book.   
Determination of direct non-medical costs. At study visits, we will collect information on 
indirect costs of medical care associated with AOM, including travel expenses for visits, 
alternate daycare expenses for siblings, as well as time costs (e.g., time for missed work).  
Determination of effectiveness. We will track days with (1) AOM symptoms with intact TMs, 
(2) tube otorrhea, and (3) medication-related adverse events or complications, by instructing 
parents to visit the study office when events are noted. The AOM-SOS scale will be 
administered at each visit. We will contact parents on Days 1-5 to determine whether 
symptoms on the AOM-SOS have resolved (score of 0 on all 5 items on Day 5), and ask 
parents to provide us with an end date. We will also contact parents on Day 12 (+/-2 days) 
to track symptoms that may not have resolved by Day 5. We will also track the occurrence of 
adverse events (PDD, diaper rash, otorrhea). To calculate quality adjusted life years 
(QALYs) for each arm, we will multiply the number of days with each outcome by the utility 
of that outcome. The first step will be to determine differences in costs and differences in 
effectiveness between the groups. We will use previously reported utility values.51  
Functional outcomes. We will use the validated OM-6 survey questionnaire,52 and CIQ to 
assess the impact of rAOM on children and their caregivers.53 The questionnaires will be 
administered at randomization and subsequently every 16 weeks (either in person or via 
phone interviews) during follow-up. The primary caregiver will complete these 
questionnaires. If the same caregiver is not present at each follow-up visit, the caregiver 
who initially completed the form will be called to gather the survey data over the phone for 
that time point. These will not be used as the primary measure because they cannot be 
easily translated into QALYs. 
• 
Proportion of children categorized as treatment failure 
• 
Severity of AOM episodes, using both the AAP definition (severe, indicated by moderate 
or severe otalgia or body temperature >39°C),5 and the AOM-SOS scores on Day 1 of 
AOM recurrences54,55 
• 
Frequency distribution of AOM recurrences 
• 
Time-to-first AOM recurrence 
• 
Proportion of AOM recurrences presenting with, respectively, intact bulging TM or tube 
otorrhea 
• 
Total days per year subjects receive systemic antimicrobials for AOM 
• 
During periods of antimicrobial therapy for AOM, (1) proportion of children with PDD, 
which will be defined as the occurrence of ≥3 watery stools on 1 day or ≥2 watery stools 
on each of 2 consecutive days, (2) diaper rash necessitating administration of topical 
antifungal therapy, and (3) otorrhea.  
• 
Mean parental/legal guardian level of satisfaction with therapy. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
26 
Parental/legal guardian level of satisfaction with the assigned study intervention will be 
compared between the two treatment groups using a one-item global assessment. Parents will 
be asked to rate their level of satisfaction with the child’s study medication at the end-of therapy 
(Day 12-14) using a 5-point scale (very dissatisfied, somewhat dissatisfied, neither satisfied nor 
dissatisfied, somewhat satisfied and very satisfied). 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
27 
4 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, clinical trial in children aged 6-35 months with 
rAOM. Its goal is to determine whether TTP compared with nonsurgical management will 
meaningfully improve the children’s AOM experience over the succeeding 2 years. A total of 
240 children diagnosed with rAOM will be enrolled at participating clinical study sites, namely, 
CHP of UPMC, Pittsburgh, PA; its affiliated Pediatric PittNet Practice-Based Research Network; 
CNMC, Washington, DC; and its affiliated CP&A, and KPAR (Kentucky Pediatric/Adult 
Research) in Bardstown, KY,. Participating clinical study sites will enroll approximately 100 
eligible children per year over a period of 2.5 years; children will be followed for a 2-year period. 
Children recruited from the target population will reflect the community at large at each 
participating site, encompassing urban (CHP and CNMC), suburban, and rural (Pediatric PittNet 
and CP&A) populations, to enhance generalizability of study findings and encourage the 
translation of study findings to clinical practice. 
Screening phase. Providers will refer potential subjects to the study who are thought to have 
had excessive numbers of episodes of AOM. There will be two phases of study participation. In 
the first, screening phase, we will obtain informed consent from the parent(s) of children who 
are felt to be at risk for rAOM, and follow them prospectively during a screening period. These 
children constitute ~20-25% of  the numbers of children we have enrolled in the placebo-
controlled study or the duration of treatment study. In this phase, our study team will We will ask 
parents to bring their children to be examined by our study team if they develop persistent 
respiratory symptoms or within 48 hours after the development of any symptom suggestive of 
AOM. This will allow us to document a minimum of one episode of AOM as evidence that the 
parent’s history of ≥3 AOM episodes in 6 months or ≥4 episodes in 12 months, as required for 
entry into the randomized phase of the study, is reasonably accurate. Episodes of AOM during 
the screening phase of the study will receive stepwise therapy with amoxicillin (90 mg/kg in two 
divided doses for 10 days), followed by amoxicillin-clavulanate (90/6.4 mg/kg in two divided 
doses for 10 days), and if the response remains inadequate, ceftriaxone (75 mg/kg 
intramuscularly, repeated in 48 hours), as recommended in the AAP guidelines.5 
 
Definition of AOM. AOM will be defined in two ways: (1) acute symptoms accompanied 
by the presence of middle-ear effusion and moderate or marked TM bulging, or slight bulging 
accompanied by either otalgia or marked TM erythema; or (2) acute symptoms associated with 
rupture of the TM with purulent otorrhea. For episodes evaluated by study personnel, acute 
symptom(s) will be defined as a score ≥2 on the AOM-SOS scale (version 4.0). For episodes 
managed by other providers, the definition of AOM will require documentation in the medical 
record of both acute symptom[s] and either TM bulging or perforation of the TM with otorrhea. 
Observation of one AOM episode by study personnel will be required for subjects to move to the 
second, randomization phase. 
Randomization phase.  
Eligibility criteria. Children will be eligible to participate in the study if they (1) are aged 6-
35 months, (2) have rAOM, defined as the occurrence of ≥3 AOM episodes in 6 months or ≥4 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
28 
episodes in 12 months with ≥1 episode in the preceding 6 months, and (3) 1 of these AOM 
episodes have been documented by trained study personnel. We have developed a multimedia 
training protocol for newly-hired study clinicians (nurse practitioners and physicians).23,26,30 Our 
eCRF will permit capture of digital images obtained otoendoscopically, and will enable study 
clinicians at participating study sites to discuss otoscopic findings as needed with Co-PIs via 
computer or cellular phone, reinforcing the validity of AOM diagnoses that determine final 
eligibility. 
Exclusion criteria. Children will be excluded if they (1) have a history of TTP, (2) have a 
chronic illness (e.g., cystic fibrosis, neoplasm, juvenile diabetes, renal or hepatic insufficiency, 
immune dysfunction, malabsorption, inflammatory bowel disease), (3) have a congenital 
anomaly that might increase the risk of recurrences (e.g., cleft palate, Down’s syndrome), (4) 
have had bilateral OME for at least 3 months in addition to rAOM, or (5) have sensorineural 
hearing loss, (6) history of adenoidectomy surgery. 
Randomization and treatment assignment. Once the study has been explained, all 
questions have been answered, and informed consent has been given, eligible subjects will 
undergo central randomization within strata based on age (6-11 months, 12-23 months and 24-
35 months) and degree/history of exposure to other children (non-exposed vs. exposed to ≥3 
children ≥10 hours/week). Children will be assigned in a 1:1 ratio to either undergo TTP or to be 
managed nonsurgically with antimicrobial treatment of individual episodes as they occur. 
Randomization information will be programmed into the eCRF so that study personnel will be 
able to schedule TTP with any of 3-4 ENT surgeons at CHP, CNMC, or KY, within 2 weeks. TT 
will be inserted under general anesthesia, using a small radial incision in the anteroinferior 
portion of the TM; a Teflon® Armstrong-type tympanostomy tube will be used. All children 
undergoing TTP will be treated with ofloxacin (Floxin® 0.3%, 5 mL) 5 drops into the external 
auditory canal twice daily for 3 days.  
Follow-up. Children enrolled in the study will be evaluated every 8 (±1) weeks, We will ask 
parents to bring their children to be examined by our study team if they develop persistent 
respiratory symptoms or within 48 hours after the development of any symptom suggestive of 
AOM. AOM will be defined as previously detailed in the screening phase (4. Study Design. 
Screening Phase. Definition of AOM.) In addition, for ears with TTs in place, the occurrence of 
otorrhea, except in the immediate postoperative period, will be considered indicative of acute 
infection provided that the otorrhea is accompanied by acute symptom(s). In such children a 
specimen for culture will be obtained. If a subject is evaluated at a non-participating clinical site 
and diagnosed with AOM, parents will be asked to bring the subject to a study site for further 
evaluation. Each study visit will include a review of adverse events, utilization of health care and 
related resources, and receipt of concomitant medications since the preceding visit. At each visit 
a targeted physical examination including pneumatic otoscopy will be conducted. If AOM is 
diagnosed, a digital TM image will be obtained otoendoscopically; digital images of TMs 
considered normal will also be obtained periodically. An NP culture will be obtained at every 
other visit, or about 3 times per year. Also at every other visit, parents will be asked to document 
indicators of functional status (see Aim 3). To determine the impact of study-related monitoring 
on health care utilization, at the end of each routine study-related visit, parents will be asked 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
29 
whether the visit either had no influence on scheduling, or prevented a primary-care provider 
visit, or induced a primary-care provider visit. At the end-of-study visit, parents will be asked to 
rate their level of satisfaction with the child’s assigned medication using a 5-point scale (very 
dissatisfied, somewhat dissatisfied, neither satisfied nor dissatisfied, somewhat satisfied and 
very satisfied).  
Findings of AOM will be counted as a recurrence if they have persisted or recurred ≥17 days 
after start of treatment for a preceding episode, because: (1) we will treat new episodes with an 
antimicrobial for 10 days, and (2) most AOM episodes occurring ≥7 days after completion of 
therapy are new infections with different pathogens rather than bacteriologic relapses (in one 
study, 59%, 74%, 86%, and 90% of infections occurring during the 1st, 2nd, 3rd and 4th week after 
therapy, respectively, were new).50 If a TT becomes obstructed, we will follow a standardized 
protocol that includes ofloxacin (5 drops twice daily for 14 days), followed by careful suction in 
clinic. In previous studies, Armstrong tubes remained in place for 12-18 months, allowing us to 
use an intention-to-treat approach for the majority of the follow-up period.44,56 As per standard 
practice, once TTs are extruded they will not be automatically replaced. However, if a TT 
becomes extruded within 6 months, it will be reinserted only if the child develops ≥2 episodes of 
AOM within 3 months. Beyond 6 months, a TT will be reinserted if the child meets criteria for 
rAOM (3 AOM episodes in 6 months, 4 AOM episodes in 12 months). 
Treatment of AOM episodes. Otorrhea occurring in children with a TT in place will be 
considered indicative of acute infection, and in such instances a specimen of the discharge for 
standard microbiologic assessment will be obtained, when possible from the tube orifice directly. 
Such children will be treated with topical ofloxacin (Floxin® 0.3%, 5 mL) 5 drops into the affected 
ear twice daily for 10 days. Persistence of otorrhea after 7 days of treatment will be considered 
inadequate response, and children so affected will be prescribed empiric amoxicillin-clavulanate 
(90/6.4 mg/kg/day in two divided doses) followed by culture-directed therapy 48 hours later. 
Children randomized to nonsurgical management will receive stepwise therapy with amoxicillin-
clavulanate (90/6.4 mg/kg in two divided doses for 10 days), and in the event of inadequate 
response, ceftriaxone (75 mg/kg intramuscularly, repeated in 48 hours), as recommended in the 
AAP guidelines.5 
Adverse events. Parents will record information regarding the frequency and consistency of 
bowel movements in a diary in order to document the occurrence of PDD, defined as the 
occurrence of ≥3 watery stools in 1 day or ≥2 watery stools per day in 2 consecutive days,  
diaper rash necessitating administration of topical antifungal therapy, and otorrhea. 
A Data and Safety Monitoring Board (DSMB) composed of outside experts regarding otitis 
media and randomized clinical trials, and a biostatistician, will be constituted. An Independent 
Safety Monitor (ISM) for Pittsburgh, PA, one for Washington, DC and one for Bardstown, KY, 
who are physicians at the respective study sites will be primarily responsible to provide 
independent safety monitoring in a timely fashion. Each ISM will be in communication with the 
PI at the participating clinical study site, the Medical Monitor, and the DSMB chair for any event 
that needs further evaluation. Reports generated for each event that summarize the status of 
the child will be reviewed by the ISM, the Medical Monitor, and the DSMB chair according to the 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
30 
DSMB charter. 
Data for this study will be reviewed by the DSMB per the DSMB charter. Trial review issues may 
include: study progress, including an assessment of data quality; outcomes; and adverse 
events/serious adverse events (AE/SAE) data, including out-of-range laboratory results; any 
pertinent new information; study procedures designed to protect the privacy of the subjects and 
the confidentiality of the data; interim analysis and final conclusions evaluating benefit-to-risk 
ratio of study participation. The DSMB may review applicable study data that include but are not 
limited to enrollment, demographics; efficacy outcomes; laboratory and safety data which may 
include AE/SAEs; concomitant medications; memory aid data; laboratory results (NP swab 
specimen cultures); TM images, otoscopic findings; and any physical examination findings. The 
DSMB will meet prior to initiation of the study, every 6 months thereafter, and after 120 children 
have completed the study (interim analysis). As an outcome of each review and meeting, the 
DSMB will make a recommendation to NIDCD at that time as to the advisability to continue, 
modify, or terminate the study. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
31 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
A total of 240 eligible children 6 to 35 months of age (inclusive) with rAOM will be enrolled in the 
randomized trial over 2.5 years to determine whether TTP compared with nonsurgical 
management will meaningfully improve the children’s AOM experience over the succeeding 2 
years. Children will be recruited from primary care practices in 5 separate geographic regions, 
Western PA, Washington, DC, and Bardstown, KYrepresenting urban, suburban and rural 
demographics. Subjects will be required to meet all of the inclusion criteria and none of the 
exclusion criteria to be eligible to participate in the study. 
Anticipated Challenges Associated with Subject Recruitment and Retention 
The proposed clinical trial requires a period of participation of more than 2 years for each 
subject. We have conducted similarly long-term trials and will implement the same methods of 
subject recruitment and retention. These include frequent meetings with practitioners at clinical 
sites, immediate availability of investigators via cell phone, immediate availability of research 
personnel at enrollment sites, electronic monitoring of subject schedules, and PittNet 
teleconferences, webinars, and meetings. The proposed study procedures present only minor 
hardship, pain, or risk to participants, principally from ear examinations and performance of NP 
cultures. TTP carries the additional risks of general anesthesia and of long-term TM sequelae, 
although these must be addressed also when children are undergoing TTP outside of research 
settings and as part of their general medical care. Our recruitment methods in previous studies 
have resulted in the enrollment of larger numbers of subjects than will be required for the 
present study. Accordingly, major obstacles to recruitment or retention are not anticipated. A 
strategy to minimize parental inconvenience and to maximize recruitment and retention involves 
conducting all study-related visits at the various PittNet and CP&A study sites as well as at the 
Primary Care Center of CHP, Goldberg Children’s Health Center at CNMC, and KPAR,. Parents 
will be reimbursed at each visit for their time and expenses, according to the local standards 
and IRB approval. As needed, taxicabs or other methods will be used to facilitate transportation. 
Finally, parents/legal guardians will be provided with a dedicated cell phone number, whereby 
investigators will be available to answer any concerns or questions parents/legal guardians 
might have. Screening logs of eligible and enrolled subjects will be maintained to detect the 
possibility of selection bias. 
5.1 
Eligibility Criteria 
Children will be eligible to participate in the study if they (1) are aged 6-35 months, (2) have 
rAOM, defined as the occurrence of ≥3 AOM episodes in 6 months or ≥4 episodes in 12 months 
with ≥1 episode in the preceding 6 months, and (3) 1of these AOM episodes have been 
documented by trained study personnel.  


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
32 
5.2 
Exclusion Criteria 
Children will be excluded if they (1) have a history of TTP; (2) have a chronic illness (e.g.,cystic 
fibrosis, neoplasm, juvenile diabetes, renal or hepatic insufficiency, immune dysfunction, 
malabsorption, inflammatory bowel disease; (3) have a congenital anomaly that might increase 
the risk of recurrences (e.g., cleft palate, Down’s syndrome); (4) have had bilateral OME for at 
least 3 months in addition to rAOM;(5) have sensorineural hearing loss and (6) history of 
adenoidectomy surgery. 
5.3 
Treatment Assignment Procedures 
Children aged 6-35 months who meet inclusion criteria for rAOM will be eligible to participate in 
the second, randomization phase of the study.  
5.3.1 Randomization Procedures 
Randomization and treatment assignment. Once the study has been explained, all 
questions have been answered, and informed consent has been given, eligible subjects will 
undergo central randomization within strata based on age (6-11 months, 12-23 months and 24-
35 months) and degree/history of exposure to other children (non-exposed vs. exposed to >3 
children >10 hours/week). Children will be assigned in a 1:1 ratio to either undergo TTP or to be 
managed nonsurgically. Randomization information will be programmed into the eCRF so that 
study personnel will be able to schedule TTP with any of 3-4 ENT surgeons at CHP, CNMC,KY, 
Rochester or WVU within 2 weeks. TTs will be inserted under general anesthesia, using a small 
radial incision in the anteroinferior portion of the TM; a Teflon® Armstrong-type tympanostomy 
tube will be used. All children undergoing TTP will be treated with ofloxacin (Floxin® 0.3%, 5 mL) 
5 drops into the external auditory canal twice daily for 3 days. 
Eligible subjects will be enrolled at each of the participating clinical study sites as they present 
for enrollment, stratified within that site by age group and degree/history of exposure to other 
children, and randomly assigned in blocks within the respective stratum to 1 of the 2 treatment 
groups. Thus, while there will certainly be differences in the numbers of enrolled subjects 
between, for example, the various participating clinical study sites, the scheme we are 
proposing has a high probability of achieving close overall balance between the two treatment 
groups unless the average number of subjects per stratum is small. 
Per International Conference on Harmonization (ICH) guideline E6: Good Clinical Practice 
(GCP), 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. The reasons why individuals 
failed screening will be recorded on the screening log. 
 
5.3.2 Masking Procedures 
Because of the nature of treatment groups, study personnel and parents of study subjects will 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
33 
not be blinded to treatment assignment. 
5.3.3 Reasons for Withdrawal 
The following events are to be considered sufficient reason for discontinuation of a subject from 
the study:  
1. Any clinical AE, laboratory abnormality, intercurrent illness, or other medical condition or 
situation such that continued participation in the study would not be in the best interest of 
the subject. 
2. Parent/legal guardian request; subjects are free to withdraw from participating in the study at 
any time upon request. 
5.3.4 Handling of Withdrawals 
Subjects who withdraw from the study after randomization will not be replaced. All subjects who 
were randomized will be included in the intent-to-treat analysis 
Subjects who are categorized as experiencing treatment failure or are withdrawn will be asked 
to return for scheduled study visits including follow-up for safety and study endpoints. 
If a parent is unwilling to continue follow-up through scheduled study visits, the child will be 
referred back to their primary care provider for continued antibiotic treatment and follow-up. 
5.3.5 Termination of Study 
The study will be completed when all enrolled subjects have completed follow-up, or when 
NIDCD following recommendations of the DSMB determines that the study needs to be 
terminated. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
34 
6 
STUDY INTERVENTION 
The study intervention consists of TTP. Children deemed to be eligible for the randomized 
phase of the study will be scheduled for evaluation by ENT specialists at each of the 
participating institutions, and for insertion of TT within 2 weeks in those assigned to receive 
TTP. TTs will be inserted under general anesthesia, using a small radial incision in the 
anteroinferior portion of the TM; a Teflon® Armstrong-type tympanostomy tube will be used. All 
children undergoing TTP will be treated with ofloxacin (Floxin® 0.3%, 5 mL) 5 drops into the 
external auditory canal twice daily for 3 days.  


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
35 
7 
STUDY SCHEDULE 
See Appendix A for the Schedule of Events table. 
7.1 
Screening Phase 
There are two phases of study participation: screening and randomization. In the screening 
phase, we will obtain informed consent from the parent(s) of children who have risk factor(s) for 
rAOM, and follow them prospectively. Risk factors would include for example: (1) age 6-35 
months; (2) early age of onset of AOM (<6 months of age), (2) a history of rAOM, (3) a current 
or recent episode of AOM, (4) episode(s) of AOM during warm-weather months (May–Oct), and 
(5) exposure to ≥3 children for ≥10 hours/week.   
Potential candidates will be referred for evaluation by clinicians at (1) the CHP Primary Care 
Center; (2) CNMC Goldberg Children’s Health Center; (3) Pediatric PittNet and other practices 
from Children’s Community Pediatrics; (4) other practices in the Pittsburgh area (5) CP&A  in 
the Washington, D.C. area (6) Bardstown, KY.. Medical records will be reviewed for potentially 
eligible children who have appointments to be evaluated. We will identify those children who are 
at risk for rAOM and those with a chief complaint of AOM-related symptoms. Parent(s) or legal 
guardian(s) will be asked by their primary care provider if they are willing to be approached by 
the research staff in order to discuss the study.  
Following a brief introduction of the study by a study clinician or research nurse, the informed 
consent process will take place with a full explanation of the study and a generous time period 
to allow the parent to read the consent document  and to enter into an exchange of questions 
and answers. Fully informed, written consent will be obtained from the parent(s) or legal 
guardian(s) after all questions and discussions have been completed and prior to conducting 
any study procedures on their child.  
Children will be followed in the screening phase until they meet criteria for rAOM, or for 12 
months if they do not develop episodes of AOM. During this phase, in order to document 
whether they experience at least one episode of AOM that would make them eligible for the 
randomized phase of the study, we will ask parents to bring their children to be examined by our 
study team if they develop persistent respiratory symptoms or within 48 hours after the 
development of any symptom suggestive of AOM. Up to 2 episodes of AOM will be accepted 
from the medical record review as protocol-defined AOM history. Documentation for such 
episodes must include one acute symptom and description of a bulging TM. Since the duration 
of middle-ear effusion is not an outcome measure of this investigation, we will not evaluate 
children following the end of therapy, unless the parent has concerns that the child has not 
improved. AOM during the screening phase will be defined as: (1) acute symptoms (at least 
one) accompanied by the presence of middle-ear effusion and moderate or marked TM bulging, 
or slight TM bulging accompanied by either otalgia or marked TM erythema, or (2) purulent 
otorrhea not due to otitis externa. Acute symptom(s) will defined by a score ≥2 on the AOM-
SOS scale (version 4.0) for episodes evaluated by study personnel, or documentation in the 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
36 
medical record by other providers for all other episodes. Observation of at least one AOM 
episode by study personnel will be required for subjects to move to the second, randomization 
phase of the study. Children who have not developed AOM for a 12-month period during the 
screening phase will be discharged from the study. 
If a participant is found to have bilateral otitis media with effusion for 6 months, we will inform 
the primary care provider who will determine subsequent management. In addition, if the parent 
has any concerns about the child’s hearing or development, we will refer the child to the primary 
care provider or ENT specialist, as appropriate.  
7.1.1 Screening Phase - Enrollment - Visit 
After receiving parental/legal guardian written consent, the following activities will be performed: 
• 
Screening criteria will be reviewed. 
• 
An AOM-SOS scale will be completed by parents, when AOM is present on enrollment, 
before any discussion of current symptoms. 
• 
We will explain to the parent(s)/legal guardian that over the next 12 months we would 
like to follow the subject when any upper respiratory symptoms develop and persist for 
≥5 days or when there is any suspicion that AOM has recurred, in order to evaluate for 
the recurrence of AOM. We will indicate that we will assess and manage episodes of 
AOM according to the standard of care and prescribe treatment as necessary.  
• 
We will initiate email reminders to be sent bi-weekly to encourage parent(s)/legal 
guardian to call study personnel with any concerns for persistent upper respiratory 
symptoms or symptoms suggestive of AOM. The email will include a question requiring a 
yes/no response concerning the presence of upper respiratory symptoms. If the parent 
indicate that their child has a cold, study staff will call the family to evaluate the need for 
a subsequent screening visit.  
• 
Baseline data will be collected about AOM risk factors (e.g., exposure to other children, 
early AOM history, AOM during warm weather months [May-Oct], and history of AOM in 
the past 6 months), and about socioeconomic factors (educational level of parents and 
type of health insurance), and demographics. 
 
• 
The child’s overall medical history will be obtained. 
 
• 
A targeted physical examination, including pneumatic otoscopy, will be performed by a 
study clinician licensed to make medical diagnoses and listed on the FDA Form 1572 as 
the site principal investigator or sub-investigator. 
• 
When possible with an episode of AOM, a nurse or clinician will capture a TM image (A 
TM image will not be able to be captured at the ED of CHP of UPMC). 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
37 
7.1.2 Screening Phase Sick Visit  
Children will be seen for a subsequent visit during the screening phase because of new, 
continuing or worsening symptoms of an upper respiratory infection (either clinical decision or 
parent request). Antibiotics will be prescribed at the investigators decision generally following a 
stepwise approach (see below) for episodes of AOM. Our study team will ask parents to bring 
their children to be examined by our study team if they develop persistent respiratory symptoms 
or within 48 hours after the development of any symptom suggestive of AOM. 
• 
AOM-SOS scale will be completed by parents before any discussion regarding current 
symptoms. 
• 
Temperature will be measured and weight obtained if clinically indicated. 
• 
We will obtain a history concerning any medical care visits at which AOM was diagnosed 
since the last study visit. 
• 
A targeted physical examination, including pneumatic otoscopy, will be performed by a 
study clinician licensed to make medical diagnoses and listed on the FDA Form 1572 as 
the site principal investigator or sub-investigator. 
• 
When possible with an episode of AOM, a nurse or clinician will capture a TM image (A 
TM image will not be able to be captured at the ED of CHP of UPMC). 
• 
Episodes of AOM occurring during the screening phase of the study will receive 
stepwise therapy with amoxicillin (90 mg/kg in two divided doses for 10 days), 
amoxicillin-clavulanate (90/6.4 mg/kg in two divided doses for 10 days), and if response 
is considered inadequate, ceftriaxone (75 mg/kg intramuscularly, repeated in 48 hours), 
as recommended in the AAP guidelines.5  
7.2 Randomization phase and treatment assignment 
Children aged 6-35 months who meet inclusion criteria for rAOM will be eligible to participate in 
the Part 2, randomization phase of the study. This enrollment visit may occur on the same day 
as a screening sick visit at which the participant became eligible for randomization. 
We will define rAOM as the occurrence of ≥3 AOM episodes in 6 months or ≥4 episodes in 12 
months with at least 1 episode in the preceding 6 months. One of these episodes must be 
documented by trained study personnel prior to enrollment in the randomized phase of the 
study.  
• 
Eligibility criteria will be reviewed. 
• 
Once the study has been explained, all questions have been answered, and informed 
consent has been obtained, eligible children will undergo central randomization within 
strata based on age (6-11 months, 12-23 months and 24-35 months) and history of 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
38 
exposure to other children (non-exposed vs. exposed to ≥3 children ≥10 hours/week). 
Children will be assigned in a 1:1 ratio either to undergo TTP or to be managed 
nonsurgically. 
• 
If a child is assigned to undergo TTP, a visit with the otolaryngologist and the surgery will 
be scheduled to take place within 2 weeks of randomization.  
• 
Randomization information will be programmed into the eCRF. 
• 
The AOM-SOS scale will be completed by parents before any discussion regarding 
current symptoms. 
• 
Vital signs (temperature, heart and respiratory rate) and weight will be measured, if 
clinically indicated. 
• 
Medical history will be reviewed. 
• 
A targeted physical examination, including pneumatic otoscopy, will be performed by a 
study clinician licensed to make medical diagnoses and listed on the FDA Form 1572 as 
the site principal investigator or sub-investigator. 
• 
A nurse, or a clinician licensed to make medical diagnoses, will capture a TM image, 
when possible.  
• 
 An NP specimen will be collected at randomization in children aged 6 to 23 months  
every 16 weeks or about three times a year. 
• 
A throat culture will be collected at randomization in children aged ≥24 months every 16 
weeks or about three times a year.  
• 
Quality of life assessment will be completed at randomization and at every other visit.  
• 
The study team will call the family after the surgery to schedule a follow-up study visit.  
Randomization Phase Follow-up every 8 weeks (7-9 weeks window) 
Children enrolled in the study will be evaluated every 8 (±1) weeks and at any time parent(s) or 
legal guardian(s) suspect the occurrence of AOM. If a subject is diagnosed with AOM at a non-
participating clinical site, parents will be asked to bring the subject to a study site within 48 
hours for further evaluation. The AOM-SOS scale will be completed by parents before any 
discussion regarding the current symptoms. 
• 
Temperature and weight will be measured if clinically indicated. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
39 
• 
A targeted physical examination, including pneumatic otoscopy, will be performed by a 
study clinician licensed to make medical diagnoses and listed on the FDA Form 1572 as 
the site principal investigator or sub-investigator.  
• 
A nurse, or a clinician licensed to make medical diagnoses will capture a TM image  for 
each episode of AOM when possible. Normal images will be obtained periodically. 
• 
An NP specimen or throat culture will be collected at every other follow-up visit or about 
three times a year. 
• 
Update history of AOM episodes. 
• 
Regarding children diagnosed with AOM--both those with intact TMs and those with tube 
otorrhea--their parents will complete an electronic memory aid daily through Day 11 to 
determine whether symptoms on the AOM-SOS have resolved (score of 0 on all 5 
items), Parents will be asked to provide an end date for symptoms. Medication-related 
adverse events (PDD, diaper rash) will be collected. 
 
• 
Parents will be asked to complete an electronic memory aid through day 11. Parents will 
be asked to provide an end date for symptoms. We will also track the occurrence of 
medication-related adverse events (PDD, diaper rash). For parents completing the paper 
memory aid, they will receive a phone call at day 5 to determine if symptoms have 
resolved. If symptoms have not resolved at day 5, parents completing the paper memory 
aid will also be called at day 12.  
• 
Otorrhea occurring in children with TT in place will be considered indicative of acute 
infection. A specimen of the discharge for standard microbiologic assessment will be 
obtained, when possible from the tube orifice directly. 
• 
Otorrhea will be treated with topical ofloxacin (Floxin® 0.3%, 5 mL) 5 drops into the 
affected ear twice daily for 10 days.  
• 
Otorrhea persisting after 7 days of treatment will be considered an inadequate response, 
and we will initiate empiric therapy with amoxicillin-clavulanate (90/6.4 mg/kg/day in two 
divided doses), followed by culture-directed therapy 48 hours later. 
• 
Children randomized to nonsurgical management will receive stepwise therapy with 
amoxicillin-clavulanate as above for 10 days, and in the event of inadequate response, 
ceftriaxone (75 mg/kg intramuscularly, repeated in 48 hours), as recommended in the 
AAP guidelines.5  
• 
Study personnel will review adverse events, utilization of health care and related 
resources, and receipt of concomitant medications since the preceding visit.  


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
40 
• 
Quality of life assessment and Caregiver Impact questionnaire will be collected at every 
other visit (i.e, about every 16 weeks). 
• 
An episode of AOM will be considered a recurrence if it has ocurred at least 17 days 
after the start of treatment for a preceding AOM episode. 
• 
If a TT becomes obstructed, we will follow a standardized protocol that includes 
ofloxacin (5 drops twice daily for 14 days), followed by careful suction in clinic.  
• 
If a TT becomes extruded within 6 months of insertion, it will be reinserted by ENT 
specialists only if the child develops at least 2 episodes of AOM within 3 months. Beyond 
6 months, a TT will be reinserted by ENT specialist only if the child meets criteria for 
rAOM (3 AOM episodes in 6 months, 4 AOM episodes in 12 months). 
• 
Follow-up visits are scheduled every 8 weeks until the end of study participation, which 
is 2 years following randomization. 
• 
To determine the impact of study-related monitoring on health care utilization, at each 
routine study-related visit, parents/legal guardians will be asked whether the study visit 
either had no influence on scheduling, or prevented, or induced a primary-care provider 
visit. 
7.2.2 Randomization Phase Sick Visit  
• 
Children will be seen for a sick visit because of new, continuing or worsening symptoms 
of an upper respiratory infection. (either clinical decision or parent request). Antibiotics 
will be prescribed as necessary for episodes of AOM according to protocol. 
• 
The AOM-SOS scale will be completed by parents before any discussion regarding           
current symptoms. 
• 
Temperature will be measured and weight obtained if clinically indicated. 
• 
A targeted physical examination, including pneumatic otoscopy, will be performed by a 
study clinician licensed to make medical diagnoses and listed on the FDA Form 1572 as 
the site principal investigator or sub-investigator. 
• 
When there is a diagnosis of AOM, a nurse, or a clinician licensed to make medical 
diagnoses, will capture a TM image when possible. A TM image will usually not be 
obtained if AOM is not diagnosed. 
• 
Otorrhea occurring in children with TT in place will be considered indicative of acute 
infection. A specimen of the discharge for standard microbiologic assessment will be 
obtained, when possible from the tube orifice directly. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
41 
• 
Otorrhea will be treated with topical ofloxacin (Floxin® 0.3%, 5 mL) 5 drops into the 
affected ear twice daily for 10 days.  
• 
Otorrhea persisting after 7 days of treatment will be considered an inadequate response, 
and we will initiate empiric treatment with amoxicillin-clavulanate (90/6.4 mg/kg/day in 
two divided doses) followed by culture-directed therapy 48 hours later. 
• 
Children randomized to nonsurgical management will receive stepwise therapy with 
amoxicillin-clavulanate as above for 10 days, and in the event of inadequate response, 
ceftriaxone (75 mg/kg intramuscularly, repeated in 48 hours), as recommended in the 
AAP guidelines.5  
• 
Parents of children diagnosed with AOM, both those with intact TMs and those with tube 
otorrhea,  will complete an electronic memory aid (or a paper memory aid in the event 
the electronic memory aid is unavailable) daily through Day 11 to determine whether 
symptoms on the AOM-SOS have resolved (score of 0 on all 5 items on Day 5). Parents 
will be asked to provide an end date for symptoms. Medication-related adverse events 
(PDD, diaper rash, otorrhea) will be collected up until day 11 in the electronic aid. In the 
event parents do not have access to e-mail or the electronic diary is not available, they 
will be given a paper diary. When completing a paper diary, the study team will call on 
day 5 to check on the child.  
• 
Parents will receive a phone call  on day 12 (+/-2 days) in order to track symptoms that 
may not have resolved on the Day 5 paper memory aid. Parents will be asked to provide 
and end date for symptoms. We will also track the occurrence of medication-related 
adverse events (PDD, diaper rash, otorrhea). Parents of children, whose health is back 
to normal at the day 5 diary entry, will not receive a phone call.  
• 
If an episode of AOM has occurred, an NP specimen or throat culture will be collected. 
• 
Study personnel will review and record selected AEs/SAEs, AOM symptom status, fever, 
diarrhea, and concomitant medications on the appropriate eCRFs. 
• 
To determine the impact of study-related monitoring on health care utilization, at each 
study sick visit, parents/legal guardians will be asked whether the study visit either had 
no influence on scheduling, or prevented, or induced a primary-care provider visit. 
• 
We will schedule an 8-week follow-up visit.  
7.3  End-of-Study Visit (± 4 weeks)  
• 
Children will undergo an end-of-study visit 2 years after randomization. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
42 
• 
The AOM-SOS scale will be completed by parents before any discussion 
regarding symptoms. 
• 
An  NP specimen or throat culture will be collected if appropriate based on the 
every other visit schedule. 
• 
A quality of life assessment and caregiver impact questionnaire will be 
completed. 
• 
Parents will be asked to rate their level of satisfaction with the child’s assigned 
medication using a 5-point scale. 
• 
A targeted physical examination, including pneumatic otoscopy, will be 
performed by a study-licensed clinician listed on the FDA Form 1572 as the site 
principal investigator or sub-investigator. 
• 
Temperature will be measured, if appropriate. 
• 
If the child is found to have AOM, treat with the provider’s choice of antibiotic. 
• 
Any recommended follow-up should occur with the child’s primary care provider. 
• 
Any adverse event that has occurred since the last visit will be recorded. 
• 
Any protocol-specific concomitantly administered medications will be recorded on 
the concomitant medication form. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
43 
8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
Medical History: Will be obtained by review of medical records and interview of the parents/legal 
guardians. The medical history is completed at the time that the subject is consented for the 
screening period and will be reconfirmed at the time of randomization to capture pertinent or 
significant medical history events including drug allergy, chronic disease, or surgery. 
Concomitant Medications: Will be obtained by review of medical records and interview of the 
parents/legal guardian. During the Screening Phase, we will inquire about the number of 
antibiotic courses the child has received during the preceding 6 months. During the 
Randomization Phase, medications taken by the subject at randomization and through the end-
of-study visit which are specific to the treatment of AOM, management of AOM symptoms and 
adverse events related to AOM treatment will be recorded (e.g., antibiotics, ear drops, 
ibuprofen, acetaminophen, topical antifungal medications). 
Physical Examination: At enrollment/randomization, vital signs (temperature, heart and 
respiratory rate) and weight (unless there is a weight measurement recorded in the previous 
month) will be measured and a targeted physical examination (including pneumatic otoscopy 
and, when possible, a capture of the TM image) will be performed by appropriate study 
personnel. At all visits following enrollment in the screening or randomization phases, pneumatic 
otoscopy will be performed, and if AOM is diagnosed, an image of the TM will be captured when 
feasible. 
Memory Aids: Parents/legal guardians will be provided with an electronic memory aid to assess 
AOM symptom status using the AOM-SOS scale. The AOM-SOS scale (version 4.0) measures 
five discrete items: tugging of ears, crying, irritability, difficulty sleeping and fever. Parents will 
be asked to rate these symptoms on enrollment in the randomized trial (Day 1), daily (Days 1- 
11) in comparison with the child’s usual state, as “none,” “a little,” or “a lot,” with corresponding 
scores of 0, 1, and 2. Thus, total scores range from 0 to 10, with higher scores indicating greater 
severity of symptoms. Frequency of bowel movements and the consistency of stools will also be 
recorded in the electronic memory aid to determine the occurrence of PDD. 
Determination of direct medical costs: Costs will be ascertained by collecting data from two 
complementary sources: parent reports and medical records. First, at each study visit (every 8 
weeks), we will ask parents about the number and type of encounters with healthcare providers 
(emergency department, hospitalizations, surgeries, ENT, primary care provider) and about 
antibiotic use. Cost of research-only visits will not be included in the calculation of the costs, 
except in cases where parents state that the visits prevented a visit for an otitis media-related 
concern. Second, we will review each subject’s medical records to ensure that all visits to health 
care professionals have been captured. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
44 
Parent questionnaires: A validated OM-6 quality of life (OM-6 QOL) survey tool will be 
administered to the parent at every other visit (every 16 weeks) after the randomization visit. A 
CIQ will be administered to the parent at every other visit (every 16 weeks) after the 
randomization visit to determine the impact of study related monitoring on health care utilization. 
At each routine study-related visit, parents/legal guardians will be asked whether the study visit 
either had no influence on scheduling, or prevented, or induced a primary care provider visit. 
Parental satisfaction with treatment: Will be evaluated using a 5-point scale (very dissatisfied, 
somewhat dissatisfied, neither satisfied nor dissatisfied, somewhat satisfied and very satisfied). 
Utilization of Health Care and Related Resources: Parents will be asked about their utilization of 
health care (ED, urgent care center, primary care provider) and related services for subjects 
enrolled in the study. The survey data will be obtained at the time of follow-up assessment 
visits. As noted above parents/legal guardians will be asked whether the study visit either had 
no influence on scheduling, or prevented, or induced a primary care provider visit. Parents will 
be also asked about the number of sick days, the number of days in which the parent(s)/legal 
guardian(s) could not work due to the child’s being sick; and the number of days on which 
alternative day-care arrangements were necessary for sick children. 
8.2 
Concomitant Medications/Treatments 
At each visit, medications taken by the child at randomization and through the end-of-study visit 
that are specific to the management of AOM or to side-effects of treatment, i.e., antibiotics, ear 
drops, ibuprofen, acetaminophen, and topical antifungal medications will be recorded.  
Special Procedures 
The study clinician at each participating study site will conduct an otoscopic examination and, 
when possible, capture an image of the TM. Participating clinical study site facilities will be 
equipped with otoendoscopes to allow capture of digital photographs into the eCRF. Although 
pneumatic otoscopic diagnosis will be considered determinative, TM images will be used to 
support classification of primary outcome (i.e., presence or absence of a need for further 
antimicrobial therapy). Similarly, by enabling study clinicians at participating study sites to 
discuss otoscopic findings with the investigators via computer or cellular phone, these images 
are expected to enhance the accuracy of both entry diagnosis and classification of treatment 
outcome. 
 
8.4 
Clinical Laboratory Evaluations 
During the screening period, children will only be evaluated for episodes of AOM; bacterial 
cultures will not be obtained. Once participants have met criteria for recurrent AOM, they enter 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
45 
into the randomization phase of the study. At the enrollment visit in this phase, we will obtain 
written informed consent for this portion of the study. We will then obtain an NP specimen in 
subjects ages 6 to 23 months from one of the nares, using a sterile, flexible, thin, nylon-flocked 
swab. A throat culture will be collected from subjects aged ≥24 months. These will be obtained 
at the time of the randomization visit, and subsequently at every other study follow-up visit (~ q 
16 weeks). Personnel will wash their hands before and after the procedure and use proper 
personal protection equipment as necessary when collecting NP swabs, specifically gloves and 
face and eye protection. Depending on children’s age, they either will be lying on the exam table 
with hands and head held securely by an assistant, or sitting in the parent’s lap. We will lift the 
subject’s chin to tip the nose slightly upward; introduce the swab gently along the floor of the 
nasal cavity, close to the nasal septum, until the pharyngeal wall is reached, usually about 4- 5 
centimeters, taking care not to insert the swab upwards. The nasal “tunnel” goes straight back 
toward the occiput and not toward the eyes. The swab will never be forced. If an obstruction is 
encountered, we will try using the other nostril; if that is unsuccessful we will not proceed 
further. The swab will be held in place for up to 5 seconds.  If at any time during follow-up the 
parent refuses to have an NP specimen obtained, we will attempt to collect a nasal swab from 
the middle turbinate in its place. 
We will place the swab into the transport tube so that the tip is immersed in the media, and 
attach preprinted labels to the transport tube including study name, visit date, subject initials and  
subject ID number. The swab can be kept at room temperature for up to 20 minutes, and then 
must be refrigerated in a specimen refrigerator until transport to the CHP Microbiology 
Laboratory (Micro Lab). When same day transport is not possible, the swab may be held 
overnight in the local site’s refrigerator, but it must be transported the following day. Per the 
current standard procedures and guidelines, it is necessary to monitor the temperature of 
equipment where specimens are stored, and record temperatures on days that specimens are 
stored in the refrigerator (no need to record on weekends or holidays). Refrigerator 
temperatures will be held at 2-8ºC while specimens are stored inside.  
When information is entered into the electronic database that the specimen has been collected, 
the Micro Lab will be so notified and the specimen will be transported. The Micro Lab will enter 
into the database the date that the swab is either plated or frozen. In the event of no growth 
from the sample, any delay of >72 hours in sample arrival to the Micro Lab will be noted by the 
Lab on the worksheet and in the electronic database. The Micro Lab will notify the PI promptly 
of any potential issues with specimen transport such as an open or spilled specimen or missing 
information on the label. All specimens will be processed upon arrival at the Micro Lab. In some 
cases, however, a specimen may be frozen temporarily until microbiological analysis can be 
performed. After NP swabs are processed, they will be frozen and stored in glycerol stock in an 
80°C freezer for potential further studies. 
NP swabs will be inoculated onto three plates: chocolate agar, 5% sheep’s blood agar with a P 
disk placed onto the TSA plate, and a chocolate agar plate, and will incubate overnight with 5% 
CO2 at 37°C. Organisms that grow on chocolate agar but not on the blood agar plates will be 
considered as potentially being H. influenzae. We will look for growth in areas proximal to 
isolates of S. aureus on blood agar plates where the presence of beta-hemolysis may allow 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
46 
growth of H. influenzae on the TSA plate. Based on the presence of hemolysis and the pattern 
of growth an assessment for potential growth of H. influenzae can be made. These colonies will 
then undergo investigation of their Gram-staining properties and colonial morphology. If they are 
Gram-negative coccobacillary rods, we will subculture colonies onto a Haemophilus Quad plate 
(Remel) to verify if they require X and V factors. Based on the presence of hemolysis and the 
pattern of growth an assessment for growth of H. influenzae can be presumed. For H. 
influenzae-like isolate characterization we will distinguish H. influenzae from H. haemolyticus. 
These closely related, but genetically distinct, strains will be distinguished by testing for 
presence of lgtC and iga by PCR.57 Strains positive for both genes will be designated H. 
influenzae and strains negative for both, H. haemolyticus. Rare strains that are discordant for 
these two genes will be considered variants. After confirmation, H. influenzae strains will tested 
by PCR for presence of capsule genes bexA and bexB, and strains positive for these genes will 
be tested for specific capsule type;58,59 bexA and bexB negative strains will be considered non-
typeable. For isolates confirmed to be H. influenzae, we will perform a cefinase test on HTM 
agar to evaluate for the presence of ß-lactamase production. Isolates of H. influenzae that are 
ß-lactamase negative will undergo antimicrobial susceptibility testing against ampicillin using the 
Remel in vitro fast MIC test according to the manufacturer’s recommendations.  
For S. pneumoniae we will inspect the 5% sheep’s blood TSA plate looking for the presence of 
alpha-hemolytic colonies. Suspicious colonies will undergo Gram-staining to confirm the 
presence of Gram-positive cocci in pairs and chains. Suspicious colonies will be sub-cultured on 
a TSA blood agar plate with a P-disk placed on the media, and colonies that show inhibition to 
the P-disk will be confirmed as S. pneumoniae. Colonies that do not have  a strong morphologic 
appearance of S. pneumoniae will be considered as non-pneumococcal strains. Isolates 
considered to be S. pneumoniae will undergo sub-culture on a TSA blood agar plate with an 
oxacillin disk for Kirby Bauer susceptibility testing. Isolates of S. pneumoniae with zones of 
inhibition of ≤19 mm to oxacillin are considered to be potentially resistant to penicillin and 
undergo broth microdilutional Micro Scan (Siemens) testing to determine specific minimum 
inhibitory concentrations (MICs) and susceptibilities to other agents using the appropriate 
recommended panel for S. pneumoniae isolates (penicillin, amoxicillin/clavulanate, ceftriaxone, 
erythromycin, clindamycin, levofloxicin and trimethoprim/sulfamethoxazole). Isolates whose 
zones of inhibition are >19 mm are considered to be penicillin-susceptible and will not undergo 
further susceptibility testing. Serotyping of confirmed isolates of S. pneumoniae is carried out 
using Statens Serum Institute kit with a Quellung reaction of serotype-specific antisera 
according to the manufacturer’s recommendation. 
For Moraxella catarrhalis we will inspect the 5% sheep’s blood TSA plate and chocolate plate 
looking for the presence of gray to white, opaque smooth, dry colonies. These colonies will be 
sub-cultured and evaluated. Colonial morphology demonstrating the appropriate appearance 
will also help identify M. catarrhalis. Suspicious colonies undergo Gram-stain to confirm the 
presence of Gram-negative diplococci. Suspicious colonies will be sub-cultured and an M. 
catarrhalis disk (containing butyrate esterase) will be used to confirm the identification. Butyrate 
hydrolysis is a key test in differentiating M. catarrhalis from Neisseria spp. Further susceptibility 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
47 
testing will not be performed for these isolates as they are all assumed to be ß-lactamase 
positive.  
 
8.4.1 Specimen Preparation, Handling, and Shipping 
All clinical microbiological samples (NP 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 Micro Lab. This laboratory will identify all organisms cultured from the 
samples. Instructions for specimen preparation, handling, and storage are included in the 
protocol-specific MOP. 
The NP swab specimens will be sent to 
Microbiology Laboratory 
Children’s Hospital of Pittsburgh of UPMC 
4401 Penn Ave.  
Pittsburgh, PA 15224 
 
Instructions for specimen shipment are included in the protocol-specific MOP. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
48 
9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
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.  
In the Screening Phase, only events meeting the criteria for SAEs are collected. In the 
Randomization Phase, select adverse events are collected from Day 1 (enrollment) through the 
end of study visit (2 years after randomization). These consist mainly of PDD, diaper rash 
necessitating the prescription of topical antifungal therapy and otorrhea. Other AEs of a severe 
nature defined below are recorded. We will record details concerning  AEs on the appropriate 
eCRF, including event description, date of onset, assessment of severity and relationship to 
study intervention, and date of resolution/stabilization. Investigators or sub-investigators with the 
training and authority to make a diagnosis and listed on the FDA Form 1572, i.e., MD, PA, 
Nurse Practitioner, DO, or DDS will assess the relationship of the AE to study intervention. AEs 
are documented appropriately regardless of relationship and 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.  
Elective procedures requiring hospitalization will not be considered SAEs.  
AEs characterized as intermittent will require documentation of onset and duration of each 
episode. The start and stop date of each reported AE will be recorded on the appropriate data 
collection form and eCRF. 
Severity of Event: All AEs will be assessed by the study clinician. At the time of an AOM 
episode, the AOM-SOS scale, a protocol-defined grading system, will measure the parent’s 
estimate of the presence and severity of five discrete items: tugging of ears, crying, irritability, 
difficulty sleeping and fever. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
49 
For events not included in the AOM-SOS scale, the following guidelines are used to quantify 
severity: 
• 
Severe: events interrupt a subject’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
• 
Life-threatening: any adverse drug experience that places the subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
Changes in the severity of an AE are documented to allow an assessment of the duration of the 
event at each level of intensity. AEs characterized as intermittent will require documentation of 
onset and duration of each episode. 
Relationship to Clinical Antibiotic Treatment or Study Intervention (TTP): The study 
clinician’s assessment of an AE's relationship to the clinical antibiotic treatment or study 
intervention (TTP) will be part of the documentation process, but will not be a factor in 
determining what is or is not reported in the study. If there is any doubt as to whether a clinical 
observation is an AE, the event will be reported. All AEs will have their relationship to clinical 
antibiotic treatment and study intervention (TTP) assessed using the terms: related or not 
related. Factors to consider in determining a causal relationship include: (1) whether the event is 
described in the investigator’s brochure or product insert; (2) whether a temporal relationship 
exists between the event and the administration of clinical antibiotic treatment or study 
intervention (TTP); (3) whether a possible alternative etiology has been identified; and (4) 
whether it is biologically plausible that the event may be related to the product. To help this 
assessment, the following guidelines will be used: 
• 
Related – There is a reasonable possibility that clinical antibiotic treatment or study 
intervention caused the adverse event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between clinical antibiotic treatment or study 
intervention (TTP) and the adverse event. 
• 
Not Related – There is not a reasonable possibility that the administration of clinical 
antibiotic treatment or study intervention 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 will be 
considered “serious” if, in the view of either the study clinician or sponsor, it results in any of the 
following outcomes: 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
50 
• 
death 
• 
a life-threatening adverse event, 
• 
inpatient hospitalization or prolongation of existing hospitalization, or 
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may nonetheless be considered serious when, based upon appropriate 
medical judgment they may jeopardize the child’s well-being 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 or blood dyscrasias or convulsions that do not result in 
inpatient hospitalization. 
All SAEs will be: 
• 
Assessed by a study physician licensed to make medical diagnoses and listed on the 
FDA Form 1572 as the principal investigator or sub-investigator at each site. 
• 
Recorded on the appropriate SAE CRF. 
• 
Followed through resolution by a study clinician licensed to make medical diagnoses and 
listed on the FDA Form 1572 as the principal investigator or sub-investigator at each 
site. 
• 
Reviewed and evaluated by an ISM, the DSMB (periodic review unless related), NIDCD, 
and the IRB. 
9.2.4 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
AE/SAEs will be documented, reported and followed appropriately. 
In order to evaluate the effect of TTP on the colonization of the nasopharynx, NP specimens will 
be obtained for culture with identification of S. pneumoniae, H. influenzae, and M. catarrhalis. In 
the absence of illness, detection of these organisms in the nasopharynx will be considered a 
normal finding, whether or not any of these organisms exhibit antimicrobial resistance. 
9.3 
Reporting Procedures 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
51 
All AE and SAE occurrences will be recorded for all subjects from Day 1 (enrollment) through 
the final study visit 2 years after randomization.  
Safety reporting will occur whenever AEs, SAEs, or PDD occur among study participants. All 
participating sites will report SAEs on the SAE Report Form to the principal investigator and the 
ISM immediately.  
SAEs related to clinical antibiotic treatment or study intervention (TTP) will be reported to the 
IRB within 24 hours of awareness at the site. Unexpected adverse reactions of moderate 
severity and related to clinical antibiotic treatment or study intervention (TTP) will be reported to 
the IRBs within 5 days. Monthly line-item reports of all SAEs and a 6-month report of all AEs will 
be submitted to the DSMB and NIDCD. The principal investigator and study team will not 
contact the DSMB or communicate with the DSMB directly. All communication and materials will 
be sent through the DSMB support contractor and NIDCD, and the study team will not review 
closed-session reports. 
9.3.1 Serious Adverse Events 
SAEs will be followed until 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. 
Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on a SAE form to the CHP Data Coordinating Center, 
at the following address: 
 Kristin YahnerData Coordinating Center 
Children’s Hospital of Pittsburgh of UPMC 
CHOB 3rd Floor 
3414 Fifth Avenue 
Pittsburgh, PA  15213 
 
SAE Hot Line: Dr. Hoberman 1-999-3277 
 
SAE FAX Phone Number:412-692-5507 
  
SAE Email: Kristin.yahner@chp.edu In addition to the SAE form, selected SAE data fields 
must will also be entered into the central database. (Please see the protocol-specific MOP for 
details regarding this procedure.) 
Other supporting documentation of the event may be requested by the NIH/NIDCD and will be 
provided as soon as possible. 
The study coordinator or principal investigator should report by telephone, fax, or email all 
deaths and life-threatening SAEs (including laryngospasm, anaphylaxis, and cardiopulmonary 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
52 
resuscitation) within 24 hours of learning of the event to the NIDCD program officer and to the 
IRB as specified in the protocol. This immediate report should be followed within 7 days by a 
detailed written report from the study coordinator or principal investigator to the NIDCD, IRB as 
required by the local IRB, and all participating investigators. All other SAEs should be reported 
to the NIDCD within 7 days, followed by a detailed written report to, NIDCD, IRB, and all 
participating investigators within 15 days. 
 
9.3.2 Reporting of Pregnancy 
Not applicable. 
9.4 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period. 
Resolution is defined as the return to pretreatment status or stabilization of the condition (the 
investigator does not expect any further improvement or worsening of the event). 
9.5 
Halting Rules 
Further enrollment and study intervention administration will be halted for DSMB review and 
recommendation if: 
• 
Any death occurs that was not the result of trauma or accident. 
The IRB and NIDCD retain the authority to suspend enrollment for the entire study at any time. 
9.6 
Safety Oversight (ISM plus DSMB) 
Safety oversight will be conducted by a DSMB which is an independent group of experts that 
review study data, monitor subject safety and advises NIDCD and the PI. DSMB members will 
be separate and independent of study personnel participating in this study and should not have 
scientific, financial or other conflict of interest related to the study. The DSMB will consist of five 
voting members including a biostatistician experienced in statistical methods for clinical trials 
and a clinician with relevant expertise. Independent Safety Monitors (ISMs) are physicians with 
relevant otitis media and/or pediatric infectious diseases expertise whose primary responsibility 
is to provide timely independent safety monitoring. The ISMs (one each for Pittsburgh, PA,  
Washington, DC and Bardstown, KY) 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 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 that occurs at the participating clinical study site in real time and 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
53 
provides an assessment to the study Co-PIs (A. Hoberman and D. Preciado) and the DSMB per 
the DSMB charter. 
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 
have no financial ties to any commercial concerns likely to be affected by the study's outcome. 
The DSMB will review study and safety data at the following time points: 
• 
At specified times during the course of study as defined in the DSMB Charter. 
• 
An interim analysis for clinical efficacy will be conducted after 120 subjects have been 
enrolled and completed follow-up. 
• 
Ad hoc when a halting rule is met, or as otherwise needed. 
The DSMB will meet regularly (usually teleconference, alternatively e-mail) to monitor the 
cumulative safety data during the participant follow-up period. Typically, the DSMB will meet 
every 6 months; and in no instance will more than 12 months elapse between DSMB review of 
cumulative safety data after the first subject has been enrolled. The DSMB will monitor the study 
according to the guidelines specified in the study protocol and the operating procedures 
established at the initial meeting, unless the DSMB determines during the course of the trial that 
modification of the guidelines is in the best interest of the study and its participants. Such a 
decision may be based on new information that emerges during the course of the study (e.g., 
publication of the results of a similar trial), recognition that initial study assumptions were 
inappropriate, or the occurrence of an unanticipated scenario. 
The DSMB will operate under the rules of an 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 also be defined 
in the charter. Procedural issues include: the board’s meeting frequency; the types and formats 
of reports it will receive from the Data Coordinating Center (DCC), the policy on whether and 
how the members may be unblinded; which 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 the 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 the trial. 
Study data will be reviewed by the DSMB according to the charter for this study. Trial review 
issues include: study progress, including an assessment of data quality (monitored monthly); 
efficacy outcomes and AE/SAE data, including out-of-range laboratory results (ongoing 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
54 
monitoring); any pertinent new information (monitored every 6 months); study procedures 
designed to protect the privacy of the subjects and the confidentiality of the data (monitored 
weekly); interim analysis, and final conclusions evaluating benefit-to-risk ratio of study 
participation. The DSMB will review applicable data that will include but not be limited to 
enrollment, demographic, and efficacy outcomes; laboratory and safety data which may include 
AE/SAEs, concomitant medications, memory aid data, and laboratory results (NP swab 
specimen cultures); TM images, otoscopic findings, and any other physical findings. Interim 
statistical reports may be generated as deemed necessary and appropriate by the PI. 
Comparative results will be presented to the DSMB in closed reports and closed sessions will 
be attended only by voting members of the DSMB and possibly a member of NIDCD staff. As an 
outcome of each review and meeting, the DSMB will make a recommendation at that time as to 
the advisability of proceeding, modifying, or terminating the study. 
SAE Reporting: The study coordinator or principal investigator should report by telephone, fax, 
or email all deaths and life-threatening SAEs (including laryngospasm, anaphylaxis, and 
cardiopulmonary resuscitation) within 24 hours of learning of the event to the NIDCD program 
officer and to the IRB as specified in the protocol. This immediate report should be followed 
within 7 days by a detailed written report from the study coordinator or principal investigator to 
the NIDCD, IRB as required by the local IRB, and all participating investigators. All other SAEs 
should be reported to the NIDCD within 7 days, followed by a detailed written report to, NIDCD, 
IRB, and all participating investigators within 15 days. 
NIDCD or the DSMB chair may convene the DSMB on an ad hoc basis according to protocol 
criteria or if there are immediate concerns regarding observations during the course of the 
study. The NIDCD Scientific Officer is empowered to stop study enrollment if adverse events 
that meet the halting criteria are reported. The NIDCD Scientific Officer 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 the study.   


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
55 
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 NIDCD, University of Pittsburgh, ICH E6 (GCP) and applicable regulatory 
guidelines, and that the study is conducted in accordance with the protocol 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 case 
report forms and informed consents, ensure GCP 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. CRAs will have reasonable access to the participating clinical study site, 
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 findings 
and discussions. Clinical monitoring reports will be submitted to the study principal investigator. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
56 
11 
STATISTICAL CONSIDERATIONS 
 
11.1 Introduction 
 
The study is a phase 3, multicenter, randomized, clinical trial in children aged 6-35 months with 
rAOM. Its goal is to determine whether TTP (experimental group) compared with nonsurgical 
management (antibiotics-treated; control group) will meaningfully improve the children’s AOM 
experience over the succeeding 2 years. This document gives details on the planned statistical 
analyses for efficacy and safety for the study.  
11.2 Objectives 
 
The primary objective of the study is to determine the efficacy of TTP for rAOM, compared with 
the efficacy of episodic nonsurgical management (i.e.conventional antibiotic therapy), in children 
aged 6 to 35 months who have reached conventional indications for TTP, i.e. at least 3 
episodes in 6 months or 4 episodes in 1 year with the most recent episode having occurred 
within the immediately preceding 6 months. Secondary objectives are (1) to examine whether 
TTP will be followed by reduced nasopharyngeal (NP) carriage rates of penicillin-nonsusceptible 
S. pneumoniae and/or β-lactamase-producing H. influenzae over the 2-year period following 
randomization and (2) to compare cost-effectiveness of TTP in these children relative to that of 
nonsurgical management.  
 
Study Design 
 
The goal of the study is to determine whether TTP compared with nonsurgical management will 
meaningfully improve the children’s AOM experience over the succeeding 2 years. A total of 
240 children diagnosed with rAOM will be enrolled at participating clinical study sites, namely, 
CHP of UPMC, Pittsburgh, PA and its affiliated Pediatric PittNet Practice-Based Research 
Network, and CNMC, Washington, DC and its affiliated CP&A as well as Bardstown, KY, 
Rochester, NY and Morgantown, WV. Participating clinical study sites are projected to enroll 
approximately 100 eligible children per year over a period of 2.5 years.  
 
Once the study has been explained, all questions have been answered, and written informed 
consent has been obtained, eligible subjects will undergo central randomization within strata 
based on age (6-11 months, 12-23 months and 24-35 months) and degree/history of exposure 
to other children (non-exposed vs exposed to ≥3 children ≥10 hours/week). Children will be 
assigned in a 1:1 ratio to either undergo TTP or to be managed nonsurgically. Randomization 
information will be programmed into the eCRF so that for children assigned to undergo TTP, 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
57 
study personnel will be able to schedule a visit with the otolaryngologist and TTP within 2 
weeks. 
 
11.3 Analysis Populations 
11.4.1 Intent-to-Treat Population (ITT) 
 
The ITT population will consist of all children who are randomized and and who receive follow-
up of any extent. No protocol violations will lead to exclusion from the intent-to-treat population. 
Children in the intent-to-treat population will be grouped according to the treatment assigned by 
the randomization procedure. This population will constitute the subjects for the primary and 
secondary efficacy analyses of study data as well as for safety analyses. 
11.4 Study Assessments 
11.5.1 Baseline Assessments 
 
The baseline visit will occur at the time of enrollment into the randomized part of the study. 
Baseline data will include demographics, medical history, medications use history, physical 
examination findings, and microbiological data (from the NP specimen collected). 
Randomization of eligible patients will occur after these assessments.  
11.5.2 Efficacy Assessments 
 
11.5.2.1 
Primary Efficacy Variable 
 
The primary study endpoint is the rate of AOM episodes during the 2-year follow-up period.  
 
11.5.2.2 
Secondary Efficacy Variables 
 
1) Treatment Failure 
Children will be deemed to have experienced treatment failure if they develop at any time any of 
the following: 
a. 2 AOM recurrences within 3 months, 3 AOM recurrences within 6 months, or 4 AOM 
recurrences within 12 months 
b. ≥3 severe AOM recurrences within 12 months, with “severe” defined as showing either: 
1. Moderate or severe otalgia or temperature >39°C 
2. AOM-SOS score >6 on Day 1 
c. Persistent MEE for ≥12 successive months 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
58 
d. Otorrhea for ≥45 days cumulatively within a 12-month period 
e. TM perforation for ≥90 days following extrusion of TT 
f. PDD (associated with antimicrobial therapy for AOM) for ≥30 days cumulatively within a 
12-month period, or treatment with intravenous fluids for PPD (associated with 
antimicrobial therapy for AOM) on ≥2 occasions 
g. Performance of TTP in children assigned originally to the nonsurgical treatment group 
h. Hospitalization for any otitis media-related reason, e.g. (1) unplanned admission 
overnight after surgery that was originally planned as ambulatory; (2) mastoiditis; (3) 
persistent otorrhea caused by pathogens resistant to oral antimicrobials; and (4) PDD 
(associated with antimicrobial therapy for AOM) severe enough to require 
hospitalization. 
i. 
Anesthesia reactions, to include laryngospasm, anaphylaxis, or a need for 
cardiopulmonary resuscitation during surgery; 
j. 
Receipt of ≥45 days cumulatively of systemic antimicrobials for AOM within a 12-month 
period 
2) Frequency of AOM recurrences 
3) Time-to-first AOM recurrence 
4) Proportion of AOM recurrences presenting with, respectively, intact bulging TM or tube 
otorrhea 
5) Total days per year subjects receive systemic antimicrobials for AOM 
6) Results of NP culture in children aged 6 to 23 months and of throat culture in children aged 
≥24 months 
7) Direct medical costs, including payments to healthcare providers and the cost of 
medications used. First, at each study visit (every 8 weeks), we will ask parents about the 
number and type of encounters with healthcare providers (ED, hospitalizations, surgeries, 
ENT, primary care provider) and about antibiotic use. Cost of research-only visits will not be 
included in the calculation of the costs, except in cases where parents state that the visits 
prevented a visit for an otitis media-related concern. Second we will review each subject’s 
medical records to ensure that all visits to health care professionals have been captured. 
We will separate costs into those related and unrelated to otitis media and its treatment. A 
clinician, masked to treatment assignment, will make this determination. This will allow us to 
compare both overall costs and costs specific to otitis media between the two treatment 
groups.  
8) Indirect medical costs: During study visits, information will be collected concerning the 
indirect costs of medical care associated with the ocurrence of otitis media, including 
expenses related to travel for visits, alternate daycare expenses for the patient and/or 
siblings, as well as time costs (e.g., time for missed work). 
11.5.3 Safety and Tolerability Assessments  
 
Adverse events – During periods of antimicrobial therapy for AOM, parents will record in a 
diary complete information regarding (1) frequency and consistency of bowel movements in 
order to ascertain the incidence of PDD, which will be defined as the occurrence of ≥3 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
59 
watery stools on 1 day or ≥2 watery stools on each of 2 consecutive days, (2) diaper rash 
necessitating administration of topical antifungal therapy, and (3) otorrhea.  
11.5 Statistical Analysis 
11.6.1 General Considerations 
 
Study data will be monitored on an on-going basis by the Data Management and Statistical Unit 
in the Division of General Academic Pediatrics at Children’s Hospital (DMSU) in Pittsburgh. The 
DMSU will inquire data clarification to the clinical sites for resolution while the study is on-going. 
Final cleaning and editing of the study database will be carried out after the last patient has 
completed follow-up. All changes to the study database will be documented. A permanent 
archive of the database will be maintained by the DMSU.  
 
Primary analysis will be based on the intent-to-treat principle, with all data analyzed according to 
children’s initial randomized assignment. 
 
All statistical tests will be two-tailed and conducted at a significance level of 0.05. For the 
primary efficacy analysis, the significance level used will be determined taking into account any 
interim analyses for efficacy. For presentation, p-values will be rounded to two significant digits. 
If the first two digits are both 0 the value will be rounded to one significant digit or reported as 
“<0.001” as appropriate. All programs used in the statistical analysis of study data 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 
undertake all the analyses of study data, using the most current version of SAS®. 
11.6.2 Interim Analysis 
 
The external DSMB for the study will meet every 6 months. The DSMB will review patient 
enrollment and safety data at every meeting. One interim analysis for efficacy is planned after 
120 children have been enrolled and completed follow-up. The interim analysis will include all 
patients whether or not they have completed the study. Type I error will be controlled by using 
the method of Fleming, Harrington and O’Brien60 and testing will be conducted at two-sided 
significance levels of 0.005 and 0.048 at the interim and final analyses, respectively. If, at the 
interim analysis, the observed value of the test statistic comparing the average number of AOM 
episodes between the two treatment groups crosses the lower boundary of -2.81 favoring the 
TTP arm (efficacy monitoring) or crosses the upper boundary of 0.52 favoring the control arm at 
the interim analysis (futility monitoring),61 it may be advisable for the DSMB to consider 
disclosing the results. Here crossing the futility boundary implies that the accumulated evidence 
up to the  80% information point would start switching its direction toward superiority of the 
control arm. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
60 
 
For both safety and efficacy interim analyses, the DMSU will present the results for the two 
treatment groups to the DSMB. The DMSU’s reports to the DSMB will include an open session 
focusing on enrollment, baseline characteristics and data completeness both by clinical site and 
overall, and a closed session where the interim safety and efficacy results will be presented 
according to treatment group. The closed session report will be seen only by the DSMB, key 
staff of the DMSU, and NIDCD personnel. At the end of each meeting, the DSMB will make a 
recommendation to NIDCD about continuing the study as planned, changing the design, or 
stopping.  
11.6.3 Subject Disposition 
 
Enrollment by study site and the number of subjects screened, randomized, withdrawn, and 
included in the analysis population (i.e. intent-to-treat [ITT]) will be reported for each treatment 
group. In addition, the number of subjects completing the study and the reasons for patient 
withdrawal will be tabulated by treatment group. 
11.6.4 Baseline (Pre-Treatment) Analyses 
 
Demographic and baseline clinical characteristics will be recorded for all patients by treatment 
group. For categorical variables, including gender, race/ethnicity, and concomitant medication 
use, frequencies and percentages will be reported. For continuous variables, including age, 
weight, and temperature, means and standard deviations will be reported. 
11.6.5 Medication Use 
 
The extent of concomitant medication use in the ITT population will be reported by treatment 
group. 
11.6.6 Efficacy Analyses 
 
Efficacy analyses will be based on comparisons between the TTP and nonsurgical management 
groups.  
 
11.6.6.1 
Primary Efficacy Analysis of the Primary Efficacy Endpoint 
 
The primary outcome variable will be the rate of AOM episodes during the 2-year follow-up 
period. The Poisson regression model with the log-link function will be used to compare mean 
rates of AOM episodes between the two treatment groups, adjusting for the stratification 
variables. Wald tests will be used to assess the prognostic importance of each variable, and, if 
necessary, treatment-by-covariate interactions will be tested by adding interaction terms one at 
a time to the models. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
61 
 
As a sensitivity analysis, the primary outcome variable will be transformed to time to multiple 
events per subject. The frailty model62 will be applied to assess the treatment effect in reduction 
in the hazard ratio, adjusting for the correlation within subjects and stratification variables. We 
will also explore whether the duration of times that the tubes are in place could be used as a 
time-dependent covariate in this analysis.  
 
11.6.6.2 
Secondary Efficacy Analyses 
 
Of the various secondary outcomes, we consider treatment failure as the most meaningful. 
Other secondary outcomes include categorical variables such as frequency distributions of 
AOM, time-to-event data, (e.g., time-to-first AOM recurrence), and continuous variables such as 
direct and indirect medical costs. For the categorical variables, a contingency table approach 
will be applied to compare two treatment groups. If a cell size is large, then a chi-squared 
approximation will be the test statistic. For binary variables, Fisher’s exact test63 will be used if 
at least one of the cell sizes is small. To adjust for confounding factors, the logistic regression 
model will be used. For the time-to-event data, the Kaplan-Meier method64 will be used to 
estimate the survival probability in the presence of censoring in each treatment group. The log-
rank test65 will be used to test formally any differences in distribution between two treatment 
groups. The Cox’s proportional hazards model66 will be utilized to compare the hazard rates 
between two groups adjusting for stratification factors and other potentially confounding factors. 
For continuous variables, if the normality assumption holds, a two-sample t- or z-test will be 
used for the group comparisons, and a linear regression model will be used to adjust for 
confounding factors. If the normality assumption does not hold, appropriate nonparametric 
counterparts such as Wilcoxon-Mann-Whitney tests for two independent samples will be used. 
All assumptions required for the statistical models will be assessed including the proportional 
hazards assumption for Cox’s model. 
 
11.6.6.3 
Statistical Analysis for Specific Aim 1 
 
We hypothesize that TTP, compared with nonsurgical management, will reduce the average 
rate of AOM episodes during the 2-year follow-up period. We will compare mean rates of AOM 
episodes between the two treatment groups by applying the Poisson regression model with the 
log-link function. A total of 240 children with rAOM will be enrolled (See Section 11.6.8 for 
sample size justification). Secondarily, estimates of change in mean rates of AOM episodes 
between the TTP and nonsurgical groups in the higher-risk and lower-risk children, respectively, 
will be useful in determining whether TTP is more beneficial for the subgroup of children at 
higher risk. The precision of these estimates will depend on the proportion of children assigned 
to the higher-risk stratum, as well as on the average number of episodes occurring in each risk 
subgroup. With the proposed sample estimate for the primary outcome (overall reduction) and 
assuming 25% attrition, if 40% of the children are at higher risk (based on our preliminary data 
in developing the rAOM-SRS), and if higher-risk children in the nonsurgical group have an 
average of 2 recurrences per year, we can estimate the difference in average number of 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
62 
episodes between treatment groups within 0.84 episode with 95% confidence (secondary 
outcome); the corresponding estimate of the difference in lower-risk children is within 0.53 
episode with 95% confidence (secondary outcome). As further extension of this secondary 
analysis, the treatment-by-risk group interaction will be formally tested. 
 
11.6.6.4 
Statistical Analysis for Specific Aim 2 
 
Secondary hypotheses of interest for Specific Aim 2 relate to bacterial resistance. We wish to 
determine whether TTP compared with nonsurgical management is associated with a lower risk 
of NP colonization with resistant AOM pathogens. More specifically, the secondary analyses will 
include (1) the proportion of children whose NP cultures at randomization are, respectively, 
either negative for S. pneumoniae and H. influenzae, or positive for penicillin-susceptible 
pathogens, or positive for one or more penicillin-nonsusceptible pathogens, who subsequently 
are found on a follow-up NP culture to harbor one or more penicillin-nonsusceptible pathogens; 
(2) the proportion of interim, non-illness visits at which a penicillin-nonsusceptible pathogen is 
recovered; and (3) for all AOM episodes, the proportions of S. pneumoniae and H. influenzae 
isolates recovered at a visit during April or May (i.e. the end of the respiratory season) that are 
penicillin nonsusceptible. For hypotheses where the proportions of subjects with a specific 
characteristic are compared, we will assume a binomial distribution. When the summary statistic 
is the proportion of AOM episodes with a specific characteristic, we will assume episodes are 
clustered within an individual and adjust for correlations when making comparisons. To 
summarize resistance, we will use the conditional odds ratio (ORC) defined by Lipsitch et al.67,68 
as the odds of having a resistant strain conditional on infection (or carriage) with that strain 
(both susceptible and resistant). This odds ratio addresses the question of community-wide 
effect of treatment on resistance as opposed to whether or not treatment makes the individual 
patient more likely to be colonized by a resistant organism. These comparisons will be made 
both (1) by randomized treatment group only, and additionally (2) by controlling for actual 
antibiotic use. 
 
11.6.6.5 
Statistical Analysis for Specific Aim 3 
 
The first step will be to determine the differences in effectiveness and the differences in costs 
between the groups. We will use analysis of covariance to compare the average AOM-SOS 
scores at day 5 and day 12 in the two groups while adjusting for baseline values. The estimated 
difference in costs divided by the estimated difference in benefits will be our first estimate of the 
cost-effectiveness of TTP. We will then construct a decision analysis model comparing TTP and 
nonsurgical management. The probability of each outcome will be based on the probabilities 
observed in the trial. We will compare the performance of treatment strategies using the 
incremental cost-effectiveness ratio, defined as the extra cost of the more expensive strategy 
divided by its extra clinical benefit in QALYs. We will conduct one-way sensitivity analyses for all 
variables and two-way sensitivity analyses on selected variables in our model to assess the 
effect of varying baseline estimates within clinically plausible ranges of cost-effectiveness. 
Variables that change the results of the incremental cost-effectiveness ratio by more than 10% 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
63 
in one-way sensitivity analyses will be selected for probabilistic sensitivity analyses, with 
parameters varied simultaneously over triangular probability distributions. Values from each 
probability distribution will be randomly selected during each of 10,000 Monte Carlo iterations. 
We will compute the percentage of Monte Carlo iterations for which a given strategy was more 
cost-effective for willingness-to-pay ceilings of $100,000/QALY gained. Analysis will be 
conducted from a societal perspective using a 2-year time horizon. A power analysis for the cost 
effectiveness analysis would not be helpful since it involves knowledge of the joint distribution of 
the difference in costs and benefits between treatment groups, which usually introduces large 
variability.69 Moreover, since we do not plan to use cost-effectiveness data for the purposes of 
inference, through probabilistic sensitivity analysis we will be estimating the likelihood that one 
strategy will be favored over others. 
 
11.6.6.6 
Missing Data 
 
Study procedures aim to minimize missing data for the primary endpoint. If missing data occurs, 
the proportion of patients with missing data for the variable will be compared between the 
treatment groups and the sensitivity to the missing data will be examined by re-analyzing the 
outcome, and any substantial discrepancy will be fully investigated. We expect very few 
intervals with no observations prior to a patient’s withdrawal from the study, so we will do no 
imputation for the few visits that are missed prior to a withdrawal. In the ITT analysis, we will 
compare the two treatment groups censoring patients at the time of withdrawal regardless of 
whether they have a functioning tube. However, we will perform a sensitivity analysis to 
investigate the impact of withdrawals on the outcome through multiple imputation where the 
covariate will include the number of recurrences of AOM prior to withdrawal. If a patient has 
missing data for a dichotomous secondary outcome variable, we will also perform a sensitivity 
analysis, first assuming that all such patients had a deleterious outcome and then assuming that 
all such patients had a favorable outcome.  
 
11.6.6.7 
Handling of Withdrawals/Crossovers 
 
Subjects who are withdrawn from the study after randomization will not be replaced. Reasons 
for withdrawals will be summarized and reported. Over the course of the trial, children in the 
nonsurgical group might for one or another reason undergo TTP. These children will continue to 
be followed in the same fashion as those who completed the study without undergoing TTP.  
The occurrence of crossovers or withdrawals might lead to a loss of statistical power and/or 
potential bias. We have partially addressed the potential loss of statistical power due to the 
dropouts by increasing the sample size. In regard to bias, we will thoroughly investigate which 
factors are related to both withdrawals and crossovers. A secondary analysis will be performed 
by censoring patients in the TTP group at the time of tube removal if their tubes are removed 
and censoring patients in the antibiotics group if they undergo TTP. This will assess the pure 
effect of the surgical procedure and the results will be compared to the previous ITT analysis. 
11.6.7 Safety and Tolerability Analyses 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
64 
 
11.6.7.1 
Adverse Events 
 
During periods of antimicrobial therapy for AOM, parents will record in a diary complete 
information regarding (1) frequency and consistency of bowel movements in order to ascertain 
the incidence of PDD, which will be defined as the occurrence of ≥3 watery stools on 1 day or 
≥2 watery stools on each of 2 consecutive days, (2) diaper rash necessitating administration of 
topical antifungal therapy, and (3) otorrhea. 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
subject who is 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. 
We will track (1) common or important adverse events potentially linked to the study-related 
therapies (e.g., PDD, generalized rash); (2) severe adverse events that require more than 
minimal medical intervention (see below); and 3) serious adverse events (see section 9.2.3).  
The occurrence of AEs will be recorded from Day 1 (enrollment) through the end-of-study visit. 
AEs will be documented regardless of relationship with clinical antibiotic treatment or study 
intervention. 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 may be recorded as an AE. The start and stop date of each 
reported AE will be recorded on the appropriate data collection form and eCRF. 
AEs will be classified as follows:  
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. 
 
 
 
 
 
 
 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
65 
Examples of the types of AEs that will be collected (contained within the heavy lines) and of AEs 
that will not be collected (gray font and marked by an asterisk), are shown in the Table below. 
** Otorrhea within 7 days of TTP will not be considered an adverse event  
Relationship to clinical antibiotic treatment or study intervention (TTP): The study clinician’s 
assessment of an AE's relationship is required prior to any unmasking. Factors that will be 
considered 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 the administration of 
clinical antibiotic treatment or study intervention (TTP); (3) a possible alternative etiology has 
been identified; and (4) it is biologically plausible that the event may be related. To help address 
this issue, the following guidelines are used: 
·         Related – There is a reasonable possibility that clinical antibiotic treatment or study 
intervention (TTP) caused the adverse event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the clinical antibiotic treatment or study 
intervention and the adverse event. 
·         Not Related – There is not a reasonable possibility that clinical antibiotic treatment or 
study intervention (TTP) caused the event. 
 
11.6.7.2 
Resource utilization 
 
We will collect data on direct costs (i.e., visits to healthcare providers; medications) and indirect 
medical costs. For direct costs, we will ask parents about the number and type of encounters 
with healthcare providers since enrollment in the study and between study visits. Similarly the 
number and types of medication used will be ascertained. For indirect costs, we will collect 
information on the costs associated with the diagnosis of AOM, including 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 follow-up visit. 
 
 
                                                                                   Categories of Adverse Events 
  
Mild 
Moderate 
Severe 
Rash 
  
*Localized rash or slight pruritus 
Generalized, moderate pruritus 
Generalized 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 
Otorrhea** 
*<7 days requiring treatment with 
topical antbiotics 
≥7 days requiring the addition of oral 
antibiotics and culture-directed therapy 
Caused by resistant bacteria 
requiring intravenous 
antibiotics 
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 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
66 
11.7.1 Sample Size Justification 
 
Hypothesizing that TTP, compared with nonsurgical management, will reduce the average 
number of AOM episodes during the 2-year follow-up period, mean rates of AOM recurrences 
will be compared between the two treatment groups by assuming a Poisson distribution. A total 
of 240 children with rAOM will be required. This number will permit, with a two-sided 
significance level of 0.05 and power >.90, detection of a 33% reduction in the average number 
of AOM recurrences in the surgical group, assuming that children receiving nonsurgical 
management will have an average of 1.5 episodes per year and estimating 25% attrition over a 
2-year period. The increase in sample size to account for dropouts is conservative in regard to 
preserving statistical power since withdrawals will still contribute some follow-up data to the 
analysis. However, it might not adjust for loss of power due to crossovers or for potential bias 
due to differential withdrawal patterns in the two treatment arms. (See Section 11.6.6.7) 
 
The Table shows the statistical powers achieved in addressing the primary hypothesis in 
Specific Aim 1 for various estimates of the number of AOM recurrences in the nonsurgical arm 
and different attrition rates. 
 
Table 1. Power estimates for finding a 33% reduction in the number of AOM recurrences in children undergoing TTP, 
with enrollment of 120 children according to baseline recurrence rates in the nonsurgical management arm and 
varying levels of attrition. 
 
 
 
6.9 Data management and quality control 
 
See Manual of Procedures.  
 
 
No. children enrolled per arm = 120 
 
No. of AOM recurrences during 2-year 
follow-up in nonsurgical arm 
Number of children evaluable per arm (attrition) 
 
90 (25%) 
84 (30%) 
78 (35%) 
72 (40%) 
 
Power 
2.0 
.90 
.88 
.85 
.82 
2.5 
.96 
.94 
.93 
.90 
3.0 
.98 
.97 
.96 
.95 
3.5 
.99 
.99 
.98 
.97 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
67 
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 NIDCD, University of Pittsburgh, and applicable regulatory 
agencies to examine (and when required by applicable law, to copy) clinical records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. 
These representatives will be permitted access to all source data. CHP and CNMC use certified, 
comprehensive 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. 
Source data are all original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these 
original documents and data records include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, TM images and subject files and 
records kept at the pharmacy, at the laboratories, and medico-technical departments involved in 
the clinical trial. 
The eCRFs provided by the DCC at the  University of Pittsburgh Center for Research on Health 
Care will be source documents. Information about each subject’s pertinent history, treatment, 
clinical findings, TM images, and results of laboratory tests will be entered into the eCRF, which 
will be the source document for most of the data collected in this study. Additional source 
documents include the patient’s medical record (i.e., utilization of health care resources), 
parent/legal guardian memory aid, and laboratory reports (received directly from the Micro lab 
and entered into the eCRF). Clinical data (including AE/SAEs, concomitant medications, 
physical assessments, memory aid information, otoscopic findings, and TM images) and 
laboratory data (including NP swab specimen cultures) will be entered into a 21 CFR Part 11-
compliant Internet eCRF provided by the University of Pittsburgh Center for Research on Health 
Care. Clinical and laboratory data will be entered directly from the source documents or during 
the parent/legal guardian interview.  


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
68 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1 Ethical Standard 
The investigators will ensure that this study 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 and/or the 
ICH E6; 62 Federal Regulations 25691 (1997). Each investigator’s Institution will hold a current 
Federal Wide Assurance (FWA) issued by OHRP for federally funded research. 
Each participating clinical study site investigator will choose subjects in accordance with the 
eligibility criteria detailed in Section 5. The investigator will not exercise selectivity so that bias is 
prevented. 
13.2 Institutional Review Board 
Prior to enrollment of subjects into this trial, the approved protocol and the informed consent 
form will be reviewed and approved by the appropriate institutional review board (IRB) listed on 
their FWA. 
The responsible official for the IRB will sign the IRB letter of approval of the protocol prior to the 
start of this trial, and a copy will be provided to NIDCD. The IRB Federal Wide Assurance 
number will be provided to NIDCD. 
Any amendments to the protocol or informed consent form will be approved before they are 
placed into use and a copy of the signed IRB letter of approval will be provided to NIDCD. 
The University of Pittsburgh Institutional Review Board (for CHP and Pediatric PittNet) and 
CNMC IRB (for both CNMC and CP&A), both registered with OHRP, will review and approve 
the protocol and informed consent form prior to commencement of subject recruitment.  
13.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the subject’s parent/legal guardian 
agreeing to have their child participate in the study, with agreement continuing throughout the 
subject’s study participation. Extensive discussion of risks and possible benefits of this therapy, 
and of the concept of placebo, will be provided to the subject’s parent/legal guardian. Consent 
forms describing in detail the study intervention, study procedures and risks will be given to the 
subject’s parent/legal guardian and written documentation of informed consent will be obtained. 
Consent forms will be IRB-approved and parent/legal guardian of subjects will be asked to read 
and review the document. Upon reviewing the document, the investigator will explain the 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
69 
research study to the subject’s parent/legal guardian and answer any questions that may arise. 
The parent/legal guardian may withdraw consent at any time throughout the course of the trial. 
A copy of the informed consent document will be given to the subject’s parent/legal guardian for 
their records. The rights and welfare of the subjects will be protected by emphasizing to the 
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 this study. 
All subjects must sign an informed consent form that complies with the requirements of 21 CFR 
Part 50 and 45 CFR 46. 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) 
Subjects in this study are between the ages of 6 and 35 months and therefore will not be able to 
provide assent. 
13.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
The study will be conducted in children aged 6 to 35 months (inclusive), an age group that 
experiences the highest incidence of AOM. As all study participants will be children, we 
anticipate an adequate number of subjects in this age group to contribute to a meaningful 
analysis. Children who meet eligibility criteria as detailed in Section 5 will be entered in the 
proposed study 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 AOM 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. 
13.5 Subject Confidentiality 
Subject confidentiality will be strictly held in trust by the investigators, their study personnel, the 
sponsor(s) and their agents. This confidentiality will be 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 the study (other than a subject’s medical records) will 
be kept confidential by the investigators and their study personnel. This information and data will 
not be used by the investigators or their study personnel for any purpose other than conducting 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
70 
the study. 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 the study; (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 17. 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 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 study data will be stored in locked file cabinets and kept in the respective research areas at 
each participating clinical study site. 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. Primary care providers will be informed about their patient’s progress periodically and 
will be notified if problems in management occur. 
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. 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. At CHP, Pediatric PittNet practices, CNMC, and 
CP&A, the respective information technology departments 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 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 jobs. 
Access will be granted based on what is minimally necessary for job completion. At all sites, 
computer user accounts and passwords will be 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 will be considered equivalent to the user’s signature. 
Additional efforts at the DCC 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 DCC requires card access or pre-
approved visitor sign-in. Physical controls for the data center include:  
• 
Locked doors with restricted, logged, card key access 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
71 
• 
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 DCC’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. 
Computers at each participating clinical study site must be compliant with CHP standards to be 
granted access to the system. All participating 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 DCC and CHP. At each participating study site, each protocol team 
member shall be assigned only 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 
during the initial log on. 
In the event that a breach is suspected of any system, administrative, or user account, all 
potentially compromised account passwords shall be immediately changed, and the appropriate 
help desk shall be notified to investigate the potential security breach. 
To protect against data loss, each participating clinical study site will adhere to the DCC 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 includes:  
• 
Regular back-ups 
• 
Secure off-site storage of tapes and documentation 
• 
Regular testing of backup media 
• 
Incident response procedures 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
72 
• 
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 for revisions of 
the contingency plans that may be necessary or advisable.. 
Any publications or presentations resulting from this work will not identify participants by name, 
but will present only aggregate data. 
13.6 Costs, Subject Compensation, Research Related Injuries 
There will be no costs to the subject or their parent/legal guardian for participation in this study. 
Subjects’ parents/legal guardians may be compensated for participation in this study. 
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.  
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 immediately contact the Principal Investigator if 
they believe that the research procedures have resulted in an injury to their child. 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. 
13.7 Study Discontinuation 
In the event that the study is discontinued, enrolled subjects will continue to be followed for 
safety assessments. Enrolled subjects will also be referred to their physician for further follow-
up. 
13.8 Future Use of Stored Specimens 
Not applicable. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
73 
14 
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 DCC as the source document to record and maintain data 
for each subject enrolled in the study. Data reported in the eCRF should also be consistent with 
other source documents (memory aid or other places where data could potentially be first 
recorded), 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 DCC will provide 
guidance to investigators on making corrections to the eCRF or other source documents. 
14.1 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. All memory aids will be reviewed with the parent at 
the time of the visit to clarify any questions about items entered. Adverse events will 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 study, the investigators must maintain 
complete and accurate documentation for the study. 
The University of Pittsburgh Center for Research on Health Care will serve as the DCC for this 
study and will be responsible for data management, quality review, analysis, and reporting of 
the study data, including uploading results to the National Library of Medicine (NLM) database. 
The DCC 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 DCC 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. NIDCD will be provided with read-only 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
74 
access to the central database in real time. If necessary, study,  data entry, and management 
personnel can view the same information simultaneously when troubleshooting a data issue. 
14.2 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 
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. The eCRF permits capture and transmission of TM 
images, which will enable clinicians at participating clinical study sites to discuss otoscopic 
findings as needed with the investigators via computer or cellular phone, further enhancing the 
accuracy of both diagnosis and classification of treatment outcome. 
Information about each subject’s pertinent history, treatment, clinical findings, TM images, and 
results of laboratory tests will be entered into the eCRF, which will be the source document for 
most of the data collected in this study. Microbiologic information related to results of NP swabs 
will be entered into the eCRF at the Infectious Diseases Research Laboratory. The memory aid 
will also be a source document from which information will be abstracted into the eCRF. Very 
limited additional information may need to be gathered from the EHR, in particular, as it relates 
to utilization of healthcare resources or adverse events. Clinical data (including AE/SAEs, 
concomitant medications, physical assessments, memory aid information, otoscopic findings, 
and TM images) and laboratory data (including NP swab specimen cultures) 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. Clinical and 
laboratory data will be entered directly from the source documents or during the parent/legal 
guardian interview. This will allow for ongoing and rapid query resolution and locking of the 
database at the close of the study. 
14.3 Types of Data 
Data for this study will include safety, laboratory and outcome measure information gathered in 
the eCRF (medical history, demographics, concomitant medications, ear examination findings 
(otoscopic findings), physical examination findings, laboratory results (NP swab specimen 
cultures), records of medical encounters at other facilities (if needed to document adverse 
events; appropriate permission forms will be obtained), and images of TMs. It will also include 
information gathered in a parent/legal guardian memory aid concerning signs and symptoms of 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
75 
AOM (AOM-SOS scale). Other data include level of parental satisfaction and utilization of 
healthcare. 
14.4 Timing/Reports 
Study data will be reviewed by the DSMB per the DSMB charter for this study. Interim statistical 
reports may be generated as deemed necessary and appropriate by NIDCD. An Interim Report 
for DSMB review will be prepared by the DSMU after 120 subjects have been enrolled and 
completed follow-up. The DSMB may receive data in aggregate and presented by treatment 
group assignment, but without the treatment group assignment identified. The DSMB may be 
unblinded to treatment group assignment, as needed, to assess safety issues. As an outcome 
of each review and meeting, the DSMB will make a recommendation at that time as to the 
advisability of continuing, modifying or terminating the study. 
Reports to the DSMB -- In general, the DMSU will prepare reports as directed by the DSMB and 
NIDCD. The contents of the reports will be determined by the DSMB and NIDCD. Additions and 
other modifications to these reports may be directed by the DSMB and/or NIDCD. 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 will receive copies of the closed session report. The reports will be 
sent by the DMSU to the NIDCD DSMB support contractor for distribution to the DSMB 
members and NIDCD at least 14 business days prior to a scheduled meeting. An Interim Report 
will be prepared by the DMSU after 120 subjects have been enrolled and completed follow-up. 
14.5 Study Records Retention 
Study documents (records and documents pertaining to the conduct of this trial, including 
eCRFs, memory aides, consent forms, and laboratory test results) will be retained for a 
minimum of 5 years in compliance with the rules of the University of Pittsburgh, for a minimum 
of 2 years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. Records will not be 
destroyed without the permission of NIDCD. Since this research involves children, all research 
records will be maintained until the youngest participants have reached the age of 23.  
14.6 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 parent/guardian, 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
76 
the investigators, or study personnel. As a result of deviations, corrective actions will be 
developed by the participating clinical study site and implemented promptly.  
These practices are consistent with ICH E6:  
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
5.1 Quality Assurance and Quality Control, section 5.1.1  
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It will be the responsibility of the participating clinical study site to use continuous vigilance to 
identify and report deviations to NIDCD via email and to the IRB per their guidelines. All 
deviations will be reported to NIDCD and ISMs on a monthly basis. Deviations will also be 
included in the DSMB reports. 
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. The investigators and their study personnel are 
responsible for knowing and adhering to their IRB/IEC requirements. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
77 
15 
PUBLICATION POLICY 
Following completion of the study, the principal investigator is expected to publish the results of 
this research in a scientific journal. All investigators funded by the NIH must submit or have 
submitted for them to the National Library of Medicine’s PubMed Central 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 that 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: 
• 
http://publicaccess.nih.gov/ 
• 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a trials-registration policy as a condition for publication. This policy requires that all clinical trials 
be registered in a public trials registry such as ClinicalTrials.gov*, which is sponsored by the 
National Library of Medicine. Other biomedical journals are considering adopting similar 
policies. Any clinical trial starting enrollment after 01 July 2005 must be registered on or before 
subject enrollment. For trials that began enrollment prior to this date, the ICMJE member 
journals will require registration by 13 September 2005, before considering the results of the trial 
for publication.  
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome. Studies designed for other purposes, 
such as to study pharmacokinetics or major toxicity (e.g., Phase I trials), would be exempt from 
this policy. 
For trials in which NIDCD is not the IND/IDE sponsor, or there is no IND/IDE, and NIDCD does 
not provide data management services, it will be the responsibility of the principal investigator 
as the “Responsible Party” to register the trial and post results in compliance with Public Law 
110-85, the Food and Drug Administration Amendments Act of 2007 (FDAAA). 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
It is the responsibility of the principal investigator to register this trial in an acceptable registry. 
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. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
78 
16 
LITERATURE REFERENCES 
 
1. 
Cullen KA, Hall MJ, Golosinskiy A. Ambulatory surgery in the United States, 2006. Natl 
Health Stat Report. 2009(11):1-25. 
2. 
Paradise JL, Rockette HE, Colborn DK, et al. Otitis media in 2253 Pittsburgh-area 
infants: prevalence and risk factors during the first two years of life. Pediatrics. 
1997;99(3):318-333. 
3. 
Marchant CD, Shurin PA, Turczyk VA, Wasikowski DE, Tutihasi MA, Kinney SE. Course 
and outcome of otitis media in early infancy: a prospective study. J Pediatr. 
1984;104(6):826-831. 
4. 
Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the first seven years 
of life in children in greater Boston: a prospective, cohort study. J Infect Dis. 
1989;160(1):83-94. 
5. 
Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of 
acute otitis media. Pediatrics. 2013;131(3):e964-999. 
6. 
Cheng J, Elden L. Evidence-based update on tympanostomy tube placement for otitis 
media in children. Ear, nose, & throat journal. 2014;93(7):236-237. 
7. 
Lous J, Ryborg CT, Thomsen JL. A systematic review of the effect of tympanostomy 
tubes in children with recurrent acute otitis media. International journal of pediatric 
otorhinolaryngology. 2011;75(9):1058-1061. 
8. 
Rappaport B, Mellon RD, Simone A, Woodcock J. Defining safe use of anesthesia in 
children. N Engl J Med. 2011;364(15):1387-1390. 
9. 
Johnston LC, Feldman HM, Paradise JL, et al. Tympanic membrane abnormalities and 
hearing levels at the ages of 5 and 6 years in relation to persistent otitis media and 
tympanostomy tube insertion in the first 3 years of life: a prospective study incorporating 
a randomized clinical trial. Pediatrics. 2004;114(1):e58-67. 
10. 
Marom T, Tan A, Wilkinson GS, Pierson KS, Freeman JL, Chonmaitree T. Trends in 
otitis media-related health care use in the United States, 2001-2011. JAMA pediatrics. 
2014;168(1):68-75. 
11. 
Gonzalez C, Arnold JE, Woody EA, et al. Prevention of recurrent acute otitis media: 
chemoprophylaxis versus tympanostomy tubes. Laryngoscope. 1986;96(12):1330-1334. 
12. 
Gebhart DE. Tympanostomy tubes in the otitis media prone child. Laryngoscope. 
1981;91(6):849-866. 
13. 
Casselbrant ML, Kaleida PH, Rockette HE, et al. Efficacy of antimicrobial prophylaxis 
and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results 
of a randomized clinical trial. The Pediatric infectious disease journal. 1992;11(4):278-
286. 
14. 
Kujala T, Alho OP, Luotonen J, et al. Tympanostomy with and without adenoidectomy for 
the prevention of recurrences of acute otitis media: a randomized controlled trial. The 
Pediatric infectious disease journal. 2012;31(6):565-569. 
15. 
Paradise JL, Bluestone CD, Colborn DK, Bernard BS, Rockette HE, Kurs-Lasky M. 
Tonsillectomy and adenotonsillectomy for recurrent throat infection in moderately 
affected children. Pediatrics. 2002;110(1 Pt 1):7-15. 
16. 
Paradise JL, Bluestone CD, Bachman RZ, et al. Efficacy of tonsillectomy for recurrent 
throat infection in severely affected children. Results of parallel randomized and 
nonrandomized clinical trials. N Engl J Med. 1984;310(11):674-683. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
79 
17. 
Paradise JL, Bluestone CD, Rogers KD, et al. Efficacy of adenoidectomy for recurrent 
otitis media in children previously treated with tympanostomy-tube placement. Results of 
parallel randomized and nonrandomized trials. JAMA. 1990;263(15):2066-2073. 
18. 
Paradise JL, Bluestone CD, Colborn DK, et al. Adenoidectomy and adenotonsillectomy 
for recurrent acute otitis media: parallel randomized clinical trials in children not 
previously treated with tympanostomy tubes. JAMA. 1999;282(10):945-953. 
19. 
Paradise JL, Feldman HM, Campbell TF, et al. Tympanostomy tubes and developmental 
outcomes at 9 to 11 years of age. N Engl J Med. 2007;356(3):248-261. 
20. 
Hoberman A, Wald ER, Hickey RW, et al. Oral versus initial intravenous therapy for 
urinary tract infections in young febrile children. Pediatrics. 1999;104(1 Pt 1):79-86. 
21. 
Hoberman A, Greenberg DP, Paradise JL, et al. Effectiveness of inactivated influenza 
vaccine in preventing acute otitis media in young children: a randomized controlled trial. 
JAMA. 2003;290(12):1608-1616. 
22. 
Investigators RT, Hoberman A, Greenfield SP, et al. Antimicrobial prophylaxis for 
children with vesicoureteral reflux. N Engl J Med. 2014;370(25):2367-2376. 
23. 
Hoberman A, Paradise JL, Rockette HE, et al. Treatment of acute otitis media in children 
under 2 years of age. N Engl J Med. 2011;364(2):105-115. 
24. 
Paradise JL. On classifying otitis media as suppurative or nonsuppurative, with a 
suggested clinical schema. J Pediatr. 1987;111(6 Pt 1):948-951. 
25. 
Hoberman A, Paradise JL. Acute otitis media: diagnosis and management in the year 
2000. Pediatr Ann. 2000;29(10):609-620. 
26. 
Shaikh N, Hoberman A, Rockette HE, Kurs-Lasky M. Development of an algorithm for 
the diagnosis of otitis media. Academic pediatrics. 2012;12(3):214-218. 
27. 
International journal of pediatric otorhinolaryngology. 1996;35:74. 
28. 
J Pediatr. 1997;132:435. 
29. 
Shaikh N, Hoberman A, Kearney DH, Yellon R. Videos in clinical medicine. 
Tympanocentesis in children with acute otitis media. N Engl J Med. 2011;364(2):e4. 
30. 
Kaleida PH, Ploof DL, Kurs-Lasky M, et al. Mastering diagnostic skills: Enhancing 
Proficiency in Otitis Media, a model for diagnostic skills training. Pediatrics. 
2009;124(4):e714-720. 
31. 
Howie VM, Ploussard JH, Sloyer J. The "otitis-prone" condition. Am J Dis Child. 
1975;129(6):676-678. 
32. 
Coffey JD, Jr. Otitis media in the practice of pediatrics. Bacteriological and clinical 
observations. Pediatrics. 1966;38(1):25-32. 
33. 
Paradise JL. Managing otitis media: a time for change. Pediatrics. 1995;96(4 Pt 1):712-
715. 
34. 
Hoberman A, Paradise JL, Shaikh N, et al. Pneumococcal resistance and serotype 19A 
in Pittsburgh-area children with acute otitis media before and after introduction of 7-
valent pneumococcal polysaccharide vaccine. Clin Pediatr (Phila). 2011;50(2):114-120. 
35. 
Hoberman A, Paradise JL, Greenberg DP, Wald ER, Kearney DH, Colborn DK. Penicillin 
susceptibility of pneumococcal isolates causing acute otitis media in children: seasonal 
variation. The Pediatric infectious disease journal. 2005;24(2):115-120. 
36. 
Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies 
after a first febrile urinary tract infection in young children. N Engl J Med. 
2003;348(3):195-202. 
37. 
Cohen R, Levy C, Bingen E, Koskas M, Nave I, Varon E. Impact of 13-valent 
pneumococcal conjugate vaccine on pneumococcal nasopharyngeal carriage in children 
with acute otitis media. The Pediatric infectious disease journal. 2012;31(3):297-301. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
80 
38. 
Wroe PC, Lee GM, Finkelstein JA, et al. Pneumococcal carriage and antibiotic 
resistance in young children before 13-valent conjugate vaccine. The Pediatric infectious 
disease journal. 2012;31(3):249-254. 
39. 
Pichichero ME, Casey JR. Emergence of a multiresistant serotype 19A pneumococcal 
strain not included in the 7-valent conjugate vaccine as an otopathogen in children. 
Jama. 2007;298(15):1772-1778. 
40. 
Doern GV, Heilmann KP, Huynh HK, Rhomberg PR, Coffman SL, Brueggemann AB. 
Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the 
United States during 1999--2000, including a comparison of resistance rates since 1994-
-1995. Antimicrobial agents and chemotherapy. 2001;45(6):1721-1729. 
41. 
Martin JM, Hoberman A, Shope T, Green M. Changes in nasopharyngeal Haemophilus 
influenzae colonization in children 6 through 23 months of age at the time of diagnosis of 
an episode of acute otitis media (1999-2012). The 52nd Annual Meeting of the Infectious 
Diseases Society of America (IDSA); October 2014; Philadelphia, PA. 
42. 
Paradise JL. Clinical trials of tonsillectomy and adenoidectomy: limitations of existing 
studies and a current effort to evaluate efficacy. South Med J. 1976;69(8):1049-1053. 
43. 
Paradise JL, Bluestone CD, Rogers KD, Taylor FH. Efficacy of adenoidectomy in 
recurrent otitis media. Historical overview and preliminary results from a randomized, 
controlled trial. Ann Otol Rhinol Laryngol Suppl. 1980;89(3 Pt 2):319-321. 
44. 
Ah-Tye C, Paradise JL, Colborn DK. Otorrhea in young children after tympanostomy-
tube placement for persistent middle-ear effusion: prevalence, incidence, and duration. 
Pediatrics. 2001;107(6):1251-1258. 
45. 
Hoberman A, Shaikh N, Bhatnagar S, et al. Factors that influence parental decisions to 
participate in clinical research: consenters vs nonconsenters. JAMA pediatrics. 
2013;167(6):561-566. 
46. 
Hoberman A. The research home: partnering with families. Academic pediatrics. 
2014;14(6):549-553. 
47. 
Paradise JL, Bluestone CD, Bachman RZ, et al. History of recurrent sore throat as an 
indication for tonsillectomy. Predictive limitations of histories that are undocumented. N 
Engl J Med. 1978;298(8):409-413. 
48. 
Paradise JL, Campbell TF, Dollaghan CA, et al. Developmental outcomes after early or 
delayed insertion of tympanostomy tubes. N Engl J Med. 2005;353(6):576-586. 
49. 
Paradise JL, Feldman HM, Campbell TF, et al. Effect of early or delayed insertion of 
tympanostomy tubes for persistent otitis media on developmental outcomes at the age of 
three years. N Engl J Med. 2001;344(16):1179-1187. 
50. 
Leibovitz E, Greenberg D, Piglansky L, et al. Recurrent acute otitis media occurring 
within one month from completion of antibiotic therapy: relationship to the original 
pathogen. The Pediatric infectious disease journal. 2003;22(3):209-216. 
51. 
Oh PI, Maerov P, Pritchard D, Knowles SR, Einarson TR, Shear NH. A cost-utility 
analysis of second-line antibiotics in the treatment of acute otitis media in children. Clin 
Ther. 1996;18(1):160-182. 
52. 
Rosenfeld RM, Bhaya MH, Bower CM, et al. Impact of tympanostomy tubes on child 
quality of life. Arch Otolaryngol Head Neck Surg. 2000;126(5):585-592. 
53. 
Boruk M, Lee P, Faynzilbert Y, Rosenfeld RM. Caregiver well-being and child quality of 
life. Otolaryngol Head Neck Surg. 2007;136(2):159-168. 
54. 
Shaikh N, Hoberman A, Paradise JL, et al. Development and preliminary evaluation of a 
parent-reported outcome instrument for clinical trials in acute otitis media. The Pediatric 
infectious disease journal. 2009;28(1):5-8. 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
81 
55. 
Shaikh N, Hoberman A, Paradise JL, et al. Responsiveness and construct validity of a 
symptom scale for acute otitis media. The Pediatric infectious disease journal. 
2009;28(1):9-12. 
56. 
Wielinga EW, Smyth GD. Comparison of the Goode T-tube with the Armstrong tube in 
children with chronic otitis media with effusion. J Laryngol Otol. 1990;104(8):608-610. 
57. 
McCrea KW, Xie J, LaCross N, et al. Relationships of nontypeable Haemophilus 
influenzae strains to hemolytic and nonhemolytic Haemophilus haemolyticus strains. J 
Clin Microbiol. 2008;46(2):406-416. 
58. 
Davis GS, Sandstedt SA, Patel M, Marrs CF, Gilsdorf JR. Use of bexB to detect the 
capsule locus in Haemophilus influenzae. J Clin Microbiol. 2011;49(7):2594-2601. 
59. 
Falla TJ, Crook DW, Brophy LN, Maskell D, Kroll JS, Moxon ER. PCR for capsular 
typing of Haemophilus influenzae. J Clin Microbiol. 1994;32(10):2382-2386. 
60. 
Fleming TR, Harrington DP, O'Brien PC. Designs for group sequential tests. Control Clin 
Trials. 1984;5:348-361. 
61. 
Anderson JR, High R. Alternatives to the standard Fleming, Harrington, and O'Brien 
futility boundary. Clin Trials. 2011;8(3):270-276. 
62. 
Vaupel JW, Manton KG, Stallard E. The impact of heterogeneity in individual frailty on 
the dynamics of mortality. Demography. 1979;16(3):439-454. 
63. 
Fisher R. On the interpretation of X2 from contingency tables, and the calculation of P. . 
J Royal Statistical Soc. 1922;85(1):87-94. 
64. 
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. Journal of 
the American Statistical Association. 1958;53:457-481. 
65. 
Peto R, Peto J. Asymptotically efficient rank invariante test procedures. Journal of the 
Royal Statistical Society-Series A. 1972;135(2):185-207. 
66. 
Cox D. Regression models and life tables. Journal of the Royal Statistical Society-Series 
B. 1972;30:248-275. 
67. 
Samore MH, Lipsitch M, Alder SC, et al. Mechanisms by which antibiotics promote 
dissemination of resistant pneumococci in human populations. Am J Epidemiol. 
2006;163(2):160-170. 
68. 
Lipsitch M. Measuring and interpreting associations between antibiotic use and penicillin 
resistance in Streptococcus pneumoniae. Clinical infectious diseases : an official 
publication of the Infectious Diseases Society of America. 2001;32(7):1044-1054. 
69. 
Petrou S, Gray A. Economic evaluation alongside randomised controlled trials: design, 
conduct, analysis, and reporting. BMJ. 2011;342:d1548. 
 
 
 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
82 
SUPPLEMENTS/APPENDICES 
APPENDIX A: SCHEDULE OF EVENTS 
 
*Vital signs/weight  - as clinically indicated 
†Nasopharyngeal or throat swab – indicated by age of participant 
‡TM image – if available when AOM dx and sometimes with  normal dx 
§AOM-SOS scale  
 
 
 
 
 
Screen 
Part 1 
Randomization 
Part 2 
 
Evaluation 
Entry 
Sick 
visit  
Entry 
Q 8-week visits 
Sick 
visit  
1 
2 
3 4 
5 6 7 
8 9 
10 
11 
 
12 
1
3 
Inclusion/ 
exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
 consent 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
exam 
X 
X 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
Vital signs 
Weight* 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical signs  
and symptoms 
 
 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
Pneumatic 
otoscopy 
X 
X 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
NP or throat 
culture† 
 
 
X 
 
X 
 
X 
 
X  
X  
X 
 
X 
X 
X 
TM image‡  
X 
 
X 
X 
X 
X X 
X X X 
X X 
 X 
X 
X 
X 
X 
AOM-SOS § 
X 
X 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
AEs 
 
 
 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
Concomitant 
medications 
 
 
X 
X 
X X X X X X X X 
X 
X 
X 
X 
X 
Parent  
questionnaires 
 
 
X 
 
X 
 
X 
 
X  
X  
X 
 
X 
X 
X 


NIDCD Protocol 1U01DC013995-01A1  
 
 
 
 
 
        
Version 3.0 
Efficacy of Tympanostomy Tubes for Children with Recurrent Acute Otitis Media  
 
             August 13, 2018 
 
 ________________________________________________________________________________________  
83 
APPENDIX B: AOM-SOS SCALE (VERSION 4.0) 
 
         
How has your child been doing? 
 
We are interested in finding out how your child has been doing.  For each question, please place 
a check () in the box corresponding to your child’s symptoms.  Please answer all questions.  
 
 
No  
 A Little  
 A Lot  
Over the past 12 h, has your child been 
tugging, rubbing, or holding the ear(s) more 
than usual? 
 
 
 
Over the past 12 h, has your child been crying 
more than usual? 
 
 
 
Over the past 12 h, has your child been more 
irritable or fussy than usual? 
 
 
 
Over the past 12 h, has your child been 
having more difficulty sleeping than usual? 
 
 
 
Over the past 12 h, has your child been 
having fever or feeling warm to touch? 
 
 
 
© University of Pittsburgh, 2014 
 
Thank you