Trial Outcomes & Findings for Efficacy of Tympanostomy Tubes for Children With Recurrent Acute Otitis Media (NCT NCT02567825)

Last Updated: 2022-07-15

Results Overview

An episode of AOM is considered a discrete occurrence if symptoms and signs persisted for, or recurred, 17 or more days after the start of antimicrobial treatment. The rate is calculated by dividing the total number of occurrences by the total number of years of follow-up. Multiple imputation was used when follow-up was incomplete.

Recruitment status

COMPLETED

Study phase

Target enrollment

250 participants

Primary outcome timeframe

Day 1 until Day 786. The mean length of actual follow-up was 662 days / 1.8 years. For each child with incomplete 2-year follow-up, multiple imputation was used and values for the remaining days/years were imputed.

Results posted on

2022-07-15

Participant Flow

Participant milestones

Participant milestones
Measure	Surgical Management Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
Overall Study STARTED	129	121
Overall Study COMPLETED	108	100
Overall Study NOT COMPLETED	21	21

Reasons for withdrawal

Reasons for withdrawal
Measure	Surgical Management Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
Overall Study No follow-up post-randomization	5	1
Overall Study Follow-up less than 23 months	16	20

Baseline Characteristics

Efficacy of Tympanostomy Tubes for Children With Recurrent Acute Otitis Media

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.	Total n=250 Participants Total of all reporting groups
Age, Customized 6-11 months	46 Participants n=5 Participants	45 Participants n=7 Participants	91 Participants n=5 Participants
Age, Customized 12-23 months	70 Participants n=5 Participants	67 Participants n=7 Participants	137 Participants n=5 Participants
Age, Customized 24-35 months	13 Participants n=5 Participants	9 Participants n=7 Participants	22 Participants n=5 Participants
Sex: Female, Male Female	42 Participants n=5 Participants	48 Participants n=7 Participants	90 Participants n=5 Participants
Sex: Female, Male Male	87 Participants n=5 Participants	73 Participants n=7 Participants	160 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	19 Participants n=5 Participants	10 Participants n=7 Participants	29 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	110 Participants n=5 Participants	111 Participants n=7 Participants	221 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	41 Participants n=5 Participants	42 Participants n=7 Participants	83 Participants n=5 Participants
Race (NIH/OMB) White	70 Participants n=5 Participants	70 Participants n=7 Participants	140 Participants n=5 Participants
Race (NIH/OMB) More than one race	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Site of Enrollment Children's Hospital of Pittsburgh (CHP)	92 Participants n=5 Participants	91 Participants n=7 Participants	183 Participants n=5 Participants
Site of Enrollment Children's National Medical Center (CNMC)	20 Participants n=5 Participants	16 Participants n=7 Participants	36 Participants n=5 Participants
Site of Enrollment Kentucky Pediatric and Adult Research (KPAR)	17 Participants n=5 Participants	14 Participants n=7 Participants	31 Participants n=5 Participants
Maternal Level of Education Less than high school	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Maternal Level of Education High school graduate or equivalent	62 Participants n=5 Participants	55 Participants n=7 Participants	117 Participants n=5 Participants
Maternal Level of Education College graduate	52 Participants n=5 Participants	56 Participants n=7 Participants	108 Participants n=5 Participants
Maternal Level of Education Unknown	9 Participants n=5 Participants	6 Participants n=7 Participants	15 Participants n=5 Participants
Type of Health Insurance Private	62 Participants n=5 Participants	62 Participants n=7 Participants	124 Participants n=5 Participants
Type of Health Insurance Public	63 Participants n=5 Participants	59 Participants n=7 Participants	122 Participants n=5 Participants
Type of Health Insurance None	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Exposure to Other Children No	26 Participants n=5 Participants	22 Participants n=7 Participants	48 Participants n=5 Participants
Exposure to Other Children Yes	103 Participants n=5 Participants	99 Participants n=7 Participants	202 Participants n=5 Participants
Otitis Media With Effusion (OME) Present at Randomization No	85 Participants n=5 Participants	71 Participants n=7 Participants	156 Participants n=5 Participants
Otitis Media With Effusion (OME) Present at Randomization Yes	44 Participants n=5 Participants	50 Participants n=7 Participants	94 Participants n=5 Participants
Estimated Risk of Recurrences of Acute Otitis Media (AOM) Low risk	63 Participants n=5 Participants	72 Participants n=7 Participants	135 Participants n=5 Participants
Estimated Risk of Recurrences of Acute Otitis Media (AOM) High risk	66 Participants n=5 Participants	49 Participants n=7 Participants	115 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 1 until Day 786. The mean length of actual follow-up was 662 days / 1.8 years. For each child with incomplete 2-year follow-up, multiple imputation was used and values for the remaining days/years were imputed.

Population: The analysis was intention-to-treat (ITT). The participants are randomized children. For each child with incomplete 2-year follow-up, the total number of episodes of acute otitis media were imputed using multivariate imputation by chained equations with 50 imputations.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Rate of Occurrence of Acute Otitis Media (AOM) Episodes Per Child-Year	1.48 Occurrences per child-year Standard Error .08	1.56 Occurrences per child-year Standard Error .08

SECONDARY outcome

Population: The analysis was ITT. The participants are randomized children. For each child with incomplete 2-year follow-up, the total number of episodes of acute otitis media were imputed using multivariate imputation by chained equations with 50 imputations.

An episode of AOM is considered a discrete occurrence if symptoms and signs persisted for, or recurred, \>=17 days after the start of antimicrobial treatment. The rate is calculated by dividing the total # of occurrences by the total # of years of follow-up. Risk of recurrences was based on early age of onset of AOM; numerous and/or frequent previous AOM episodes; receipt of multiple courses of antibiotic; eligibility for enrollment first evident during warm-weather months; parental characterization of previous AOM episodes as severe; eligibility for enrollment despite nonexposure to other young children; moderate or marked tympanic membrane (TM) bulging with previous AOM episodes; most previous AOM episodes in both ears; and a high score on the Acute Otitis Media Severity of Symptom scale (with scores ranging from 0 to 10 and higher scores indicating greater severity of symptoms) during screening and/or at enrollment. Multiple imputation was used when follow-up was incomplete.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Rate of Occurrence of Acute Otitis Media (AOM) Episodes Per Child-Year According to the Estimated Risk of Acute Otitis Media (AOM) Recurrences at Enrollment Children considered at high risk of AOM recurrence	1.67 Occurrences per child-year Standard Error 0.11	1.56 Occurrences per child-year Standard Error 0.13
The Rate of Occurrence of Acute Otitis Media (AOM) Episodes Per Child-Year According to the Estimated Risk of Acute Otitis Media (AOM) Recurrences at Enrollment Children considered at low risk of AOM recurrence	1.28 Occurrences per child-year Standard Error 0.10	1.56 Occurrences per child-year Standard Error 0.10

SECONDARY outcome

Timeframe: Day 1 until Day 786. For children completing the study, the mean length of follow-up was 726 days.

Population: The analysis was ITT. The participants are randomized children having follow-up greater than or equal to 23 months.

An episode of AOM is considered a discrete occurrence if symptoms and signs persisted for, or recurred, 17 or more days after the start of antimicrobial treatment. Children with at least 23 months of follow-up were considered to have completed the study.

Outcome measures

Outcome measures
Measure	Surgical Management n=108 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=100 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Frequency Distribution of AOM Episodes Among Children Completing the Study Number of cumulative episodes = 0	17 Participants	12 Participants
The Frequency Distribution of AOM Episodes Among Children Completing the Study Number of cumulative episodes = 1 or 2	41 Participants	41 Participants
The Frequency Distribution of AOM Episodes Among Children Completing the Study Number of cumulative episodes = 3 or 4	24 Participants	29 Participants
The Frequency Distribution of AOM Episodes Among Children Completing the Study Number of cumulative episodes >= 5	26 Participants	18 Participants

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children with follow-up.

Parents used the Acute Otitis Media Severity of Symptoms (AOM-SOS) scale (version 4.0) to rate each of 5 symptoms as none, a little, or a lot, with corresponding scores of 0, 1, and 2. Total scores range from 0 to 10; higher scores indicate greater severity of symptoms. AOM episodes were categorized as likely severe if the parent described the child as having moderate or severe otalgia (a lot of ear tugging), temperature ≥39°C, or an AOM-SOS scale score \>6 Day 1 of the episode. TF is defined as frequent AOM recurrences (2 in 3 months, 3 in 6 or 4 in 12); ≥3 likely severe AOM recurrences, receipt of ≥45 cumulative days of systemic antimicrobial treatment for AOM, otorrhea for ≥45 cumulative days or diarrhea associated with antimicrobial treatment for ≥30 cumulative days, respectively, in 12 months; persistent effusion for ≥12 successive months; TM perforation for ≥90 days; AOM related hospitalization; anesthesia reactions; and tubes in children randomized to nonsurgical management.

Outcome measures

Outcome measures
Measure	Surgical Management n=124 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=120 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Children Experiencing Treatment Failure (TF) Experienced failure	56 Participants	74 Participants
The Distribution of Children Experiencing Treatment Failure (TF) Did not experience failure	68 Participants	46 Participants

SECONDARY outcome

Timeframe: Day 1 until Day 786. The mean length of follow-up was 662 days / 21.8 months.

Population: The analysis was ITT. The participants are randomized children.

The time to the first episode of AOM is defined as the time, expressed in months, from randomization until the first episode of AOM.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Time to the First Episode of AOM	4.34 Months Interval 2.99 to 5.88	2.33 Months Interval 1.61 to 3.12

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children having at least one episode of AOM.

The American Academy of Pediatrics clinical practice guideline concerning the management of AOM refers to children with "severe signs or symptoms" as those with "moderate or severe otalgia or otalgia for \>= 48 hours or temperature 39°C (102.2°F) or higher." To simulate that definition, scores are used from the 5-item Acute Otitis Media Severity of Symptoms (AOM-SOS) scale (version 4.0) in which parents are asked to rate symptoms, as compared with the child's usual state, as none, a little, or a lot, with corresponding scores of 0, 1, and 2. Total scores range from 0 to 10, with higher scores indicating greater severity of symptoms. AOM episodes are categorized as "probably severe" if the parent described the child as having had moderate or severe otalgia (a lot of ear tugging; i.e. a score of 2), temperature \>=39°C, or an AOM-SOS scale score \>6 on Day 1 of the episode. If not "probably severe", then the episode is categorized as "probably nonsevere".

Outcome measures

Outcome measures
Measure	Surgical Management n=336 Episodes of AOM Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=333 Episodes of AOM Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of AOM Episodes Categorized as Probably Severe or Probably Nonsevere Probably nonsevere	180 Episodes of AOM	168 Episodes of AOM
The Distribution of AOM Episodes Categorized as Probably Severe or Probably Nonsevere Probably severe	156 Episodes of AOM	165 Episodes of AOM

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children having at least one episode of AOM.

The presence of either tympanic membrane bulging or tympanic membrane perforation with purulent otorrhea, in addition to documentation of symptoms, is required for each episode of AOM.

Outcome measures

Outcome measures
Measure	Surgical Management n=336 Episodes of AOM Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=333 Episodes of AOM Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of AOM Episodes Presenting With Tympanic Membrane Bulging or Otorrhea Episodes presenting with tympanic membrane bulging	86 Episodes of AOM	248 Episodes of AOM
The Distribution of AOM Episodes Presenting With Tympanic Membrane Bulging or Otorrhea Episodes presenting with otorrhea	250 Episodes of AOM	85 Episodes of AOM

SECONDARY outcome

Timeframe: Day 1 until Day 786. The mean length of follow-up was 662 days / 1.8 years.

Population: The analysis was ITT. The participants are randomized children.

Adverse events, including tube-associated otorrhea, were collected from enrollment through the end of study. Each study visit included a review of adverse events. Any such event that occurred since the previous visit was recorded, including the date of onset and the date of resolution. For each child, the days per year of tube otorrhea is calculated by dividing the total number of days of tube otorrhea (based on dates of onset and resolution) by the total number of years of follow-up.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Mean Days Per Year Children Experience Tube Otorrhea	7.96 Days per year Standard Error 1.10	2.83 Days per year Standard Error 0.78

SECONDARY outcome

Timeframe: Day 1 until Day 786. The mean length of follow-up was 662 days / 1.8 years.

Population: The analysis was ITT. The participants are randomized children.

For a given child, if a day of follow-up coincides with a study visit, the status of the right and left TMs are recorded at the ear exam. If a day of follow-up does not coincide with a study visit the status of each TM is assumed to be the same as the status on the prior day. Scores are used from the 5-item Acute Otitis Media Severity of Symptoms (AOM-SOS) scale (version 4.0) in which parents are asked to rate symptoms, as compared with the child's usual state, as none, a little, or a lot, with corresponding scores of 0, 1, and 2. Total scores range from 0 to 10, with higher scores indicating greater severity of symptoms. Scores are recorded at study visits and on diaries. The total number of days with an intact TM and a AOM-SOS score greater than or equal to 1 is divided by the total number of years of follow-up to arrive at the days per year with AOM symptoms and an intact TM.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Mean Days Per Year Children Experience AOM Symptoms With an Intact Tympanic Membrane (TM)	2.00 Days per year Standard Error 0.29	8.33 Days per year Standard Error 0.59

SECONDARY outcome

Timeframe: Day 1 until Day 786. The mean length of follow-up was 662 days / 1.8 years.

Population: The analysis was ITT. The participants are randomized children.

Systemic antibiotics include Amoxicillin-Clavulanate, Ceftriaxone, Cefdinir, Amoxicillin, Azithromycin, Clindamycin, Levofloxacin, Bactrim, Cefprozil, Omnicef and Trimethoprim-Sulfamethoxazole. The days per year, for each child, is calculated by dividing the total number of days the child receives systemic antimicrobials for AOM (based on the recorded start and stop dates) by the total number of years of follow-up.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Mean Days Per Year Children Receive Systemic Antimicrobials for AOM	8.76 Days per year Standard Error 0.94	12.92 Days per year Standard Error 0.90

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was intention-to-treat (ITT). The participants are randomized children.

PDD is defined as the occurrence of three or more watery stools on 1 day or two or more watery stools on each of 2 consecutive days. Adverse events, including PDD, were collected from enrollment through the end of study. Each study visit included a review of medication-related adverse events. Any such event that occurred since the previous visit was recorded.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported PDD was not reported	108 Participants	87 Participants
The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported PDD was reported	21 Participants	34 Participants

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children.

Diaper dermatitis is defined as diaper rash necessitating administration of topical antifungal therapy. Adverse events, including diaper dermatitis, were collected from enrollment through the end of study. Each study visit included a review of medication-related adverse events. Any such event that occurred since the previous visit was recorded.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Children for Whom Diaper Dermatitis Was Reported Diaper dermatitis was reported	25 Participants	33 Participants
The Distribution of Children for Whom Diaper Dermatitis Was Reported Diaper dermatitis was not reported	104 Participants	88 Participants

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Children for Whom Tube Otorrhea Was Reported Tube otorrhea was reported	94 Participants	34 Participants
The Distribution of Children for Whom Tube Otorrhea Was Reported Tube otorrhea was not reported	35 Participants	87 Participants

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: Children with a nasopharyngeal or throat culture at enrollment and at least 1 follow-up nasopharyngeal or throat culture

Throat specimens were obtained mainly from children older than 24 months of age. The penicillin-nonsusceptible pathogens considered are penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae and ß-lactamase-positive Haemophilus influenzae. Susceptibility to penicillin was defined as follows: susceptible as a minimum inhibitory concentration (MIC) of \<0.1 μg/mL; intermediate as an MIC of 0.1 to 1μg/mL; and resistant as an MIC of \>1 μg/mL.

Outcome measures

Outcome measures
Measure	Surgical Management n=113 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=113 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Children With a Penicillin-Nonsusceptible Nasopharyngeal or Throat Isolate At Any Follow-up Visit According to the Colonization Status at Enrollment No pathogens at enrollment · No penicillin-nonsusceptible isolate at a follow-up visit	12 Participants	11 Participants
The Distribution of Children With a Penicillin-Nonsusceptible Nasopharyngeal or Throat Isolate At Any Follow-up Visit According to the Colonization Status at Enrollment No pathogens at enrollment · Penicillin-nonsusceptible isolate at a follow-up visit	25 Participants	24 Participants
The Distribution of Children With a Penicillin-Nonsusceptible Nasopharyngeal or Throat Isolate At Any Follow-up Visit According to the Colonization Status at Enrollment Positive only for at least 1 penicillin-susceptible pathogen at enrollment · Penicillin-nonsusceptible isolate at a follow-up visit	22 Participants	20 Participants
The Distribution of Children With a Penicillin-Nonsusceptible Nasopharyngeal or Throat Isolate At Any Follow-up Visit According to the Colonization Status at Enrollment Positive only for at least 1 penicillin-susceptible pathogen at enrollment · No penicillin-nonsusceptible isolate at a follow-up visit	11 Participants	15 Participants
The Distribution of Children With a Penicillin-Nonsusceptible Nasopharyngeal or Throat Isolate At Any Follow-up Visit According to the Colonization Status at Enrollment Positive for at least 1 penicillin-nonsusceptible pathogen at enrollment · Penicillin-nonsusceptible isolate at a follow-up visit	38 Participants	34 Participants
The Distribution of Children With a Penicillin-Nonsusceptible Nasopharyngeal or Throat Isolate At Any Follow-up Visit According to the Colonization Status at Enrollment Positive for at least 1 penicillin-nonsusceptible pathogen at enrollment · No penicillin-nonsusceptible isolate at a follow-up visit	5 Participants	9 Participants

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children with at least one episode of AOM at which a nasopharyngeal or throat culture is obtained.

Throat specimens were obtained mainly from children older than 24 months of age. The penicillin-nonsusceptible pathogens considered are penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae (S. pn) and ß-lactamase-positive Haemophilus influenzae (H. flu). Susceptibility to penicillin was defined as follows: susceptible as a minimum inhibitory concentration (MIC) of \<0.1 μg/mL; intermediate as an MIC of 0.1 to 1μg/mL; and resistant as an MIC of \>1 μg/mL.

Outcome measures

Outcome measures
Measure	Surgical Management n=173 Episodes of AOM Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=196 Episodes of AOM Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Nonsusceptible Nasopharyngeal or Throat Pathogens Recovered at Episodes of AOM Any nonsusceptible pathogen (nonsusceptible S. pn and/or Beta-lactamase positive H. flu)	66 Episodes of AOM	64 Episodes of AOM
The Distribution of Nonsusceptible Nasopharyngeal or Throat Pathogens Recovered at Episodes of AOM No nonsusceptible pathogen	107 Episodes of AOM	132 Episodes of AOM

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children with at least one routine non-illness visit at which a nasopharyngeal or throat culture is obtained.

Throat specimens were obtained mainly from children older than 24 months of age. The penicillin-nonsusceptible pathogens considered are penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae (S. pm) and ß-lactamase-positive Haemophilus influenzae (H. flu). Susceptibility to penicillin was defined as follows: susceptible as a minimum inhibitory concentration (MIC) of \<0.1 μg/mL; intermediate as an MIC of 0.1 to 1μg/mL; and resistant as an MIC of \>1 μg/mL.

Outcome measures

Outcome measures
Measure	Surgical Management n=485 Routine non-illness visits Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=447 Routine non-illness visits Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Nonsusceptible Nasopharyngeal or Throat Pathogens Recovered at Routine Non-Illness Visits No nonsusceptible pathogen	369 Routine non-illness visits	349 Routine non-illness visits
The Distribution of Nonsusceptible Nasopharyngeal or Throat Pathogens Recovered at Routine Non-Illness Visits Any nonsusceptible pathogen (nonsusceptible S. pn and/or Beta-lactamase positive H. flu)	116 Routine non-illness visits	98 Routine non-illness visits

SECONDARY outcome

Timeframe: April 1 to May 31, each of the 2 years of follow-up. The mean length of follow-up was 111 days / 3.7 months.

Population: The analysis was ITT. The participants are randomized children with at least one episode of AOM late during the respiratory season (April-May) at which a nasopharyngeal or throat culture is obtained

Throat specimens were obtained mainly from children older than 24 months of age. The penicillin-nonsusceptible pathogens considered are penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae (S. pn) and ß-lactamase-positive Haemophilus influenzae (H. flu). Susceptibility to penicillin was defined as follows: susceptible as a minimum inhibitory concentration (MIC) of \<0.1 μg/mL; intermediate as an MIC of 0.1 to 1μg/mL; and resistant as an MIC of \>1 μg/mL.

Outcome measures

Outcome measures
Measure	Surgical Management n=37 Episodes of AOM Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=43 Episodes of AOM Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Nonsusceptible Nasopharyngeal or Throat Pathogens Recovered at AOM Episodes Late During the Respiratory Season (April-May) Any nonsusceptible pathogen (nonsusceptible S. pn and/or Beta-lactamase positive H. flu)	16 Episodes of AOM	16 Episodes of AOM
The Distribution of Nonsusceptible Nasopharyngeal or Throat Pathogens Recovered at AOM Episodes Late During the Respiratory Season (April-May) No nonsusceptible pathogen	21 Episodes of AOM	27 Episodes of AOM

SECONDARY outcome

Timeframe: The end-of-study visit. The mean day for this visit was 726.

Population: The analysis was ITT. The participants are randomized children who completed the study and whose parent rated their level of satisfaction.

At the end-of-study visit, parents were asked to rate their level of satisfaction with their child's assigned management using a 5-point scale with higher numbers indicating greater satisfaction, specifically 1 = very dissatisfied, 2 = somewhat dissatisfied, 3 = neither satisfied nor dissatisfied, 4 = somewhat satisfied, and 5 = very satisfied.

Outcome measures

Outcome measures
Measure	Surgical Management n=105 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=96 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Mean Score Representing Parental Satisfaction With Clinical Management	4.64 Score on a scale Standard Error 0.10	4.43 Score on a scale Standard Error 0.13

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children having at least one parent report.

Health care encounters, indicators of medical resource use, were ascertained from parent reports. At scheduled study visits, every 8 weeks after randomization. and at interim sick study visits, parents were asked about encounters with healthcare providers, including hospitalizations and visits to emergency departments, urgent care, and primary care providers, since the previous study visit.

Outcome measures

Outcome measures
Measure	Surgical Management n=1635 Number of parent reports Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=1628 Number of parent reports Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Parent Reports Indicating At Least One Health Care Encounter Since the Previous Study Visit as an Indicator of Medical Resource Use Number of reports indicating at least one health care encounter since the previous study visit	738 Number of parent reports	672 Number of parent reports
The Distribution of Parent Reports Indicating At Least One Health Care Encounter Since the Previous Study Visit as an Indicator of Medical Resource Use Number of reports indicating no health care encounter since the previous study visit	897 Number of parent reports	956 Number of parent reports

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children having at least one parent report.

Occurrences of parent missing work due to child's illness, an indicator of non-medical resource use, was ascertained from parent reports at scheduled study visits, every 8 weeks after randomization, and at interim sick study visits.

Outcome measures

Outcome measures
Measure	Surgical Management n=1635 Number of parent reports Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=1628 Number of parent reports Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Reported Occurrences of a Parent Missing Work Due to Child's Illness, as an Indicator of Non-Medical Resource Use Number of reports indicating a parent missed work due to child's illness	286 Number of parent reports	256 Number of parent reports
The Distribution of Reported Occurrences of a Parent Missing Work Due to Child's Illness, as an Indicator of Non-Medical Resource Use Number of reports indicating parent did not miss work due to child's illness	1317 Number of parent reports	1342 Number of parent reports
The Distribution of Reported Occurrences of a Parent Missing Work Due to Child's Illness, as an Indicator of Non-Medical Resource Use Number of reports for which the parent did not answer the question	32 Number of parent reports	30 Number of parent reports

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children having at least one parent report.

Occurrences of the need for special childcare arrangements due to child's illness, an indicator of non-medical resource use, was ascertained from parent reports at scheduled study visits, every 8 weeks after randomization, and at interim sick study visits.

Outcome measures

Outcome measures
Measure	Surgical Management n=1635 Number of parent reports Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=1628 Number of parent reports Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Distribution of Reported Occurrences of the Need for Special Childcare Arrangements Due to Child's Illness, as an Indicator of Non-Medical Resource Use Number of reports indicating the need for special child care arrangements due to child's illness	231 Number of parent reports	195 Number of parent reports
The Distribution of Reported Occurrences of the Need for Special Childcare Arrangements Due to Child's Illness, as an Indicator of Non-Medical Resource Use Number of reports indicating no need for special child care arrangements due to child's illness	1402 Number of parent reports	1429 Number of parent reports
The Distribution of Reported Occurrences of the Need for Special Childcare Arrangements Due to Child's Illness, as an Indicator of Non-Medical Resource Use Number of reports for which the parent did not answer the question	2 Number of parent reports	4 Number of parent reports

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children having at least one parent report.

The OM-6 is a 6 item quality of life assessment addressing physical suffering, hearing loss, speech impairment, emotional distress, activity limitations and caregiver concerns. Responses are regarded on an ordinal scale ranging from 1 (no problem) to 7 (greatest problem). The average response, i.e., score, for these 6 items is calculated. The overall child's quality of life (QOL) score, also captured on the OM-6, is expressed on an ordinal response scale that ranges from 0 (worst quality of life) to 10 (best quality). A OM-6 is administered to the parent every 16 weeks after randomization and occasionally at sick visits.

Outcome measures

Outcome measures
Measure	Surgical Management n=890 Number of parent reports Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=830 Number of parent reports Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Mean Scores on the 6 Item Quality of Life Survey Questionnaire (OM-6) OM-6 survey score	1.5 Score on a scale Standard Error 0.03	1.55 Score on a scale Standard Error 0.03
The Mean Scores on the 6 Item Quality of Life Survey Questionnaire (OM-6) OM-6 survey--Children's overall QOL score	8.45 Score on a scale Standard Error 0.07	8.37 Score on a scale Standard Error 0.07

SECONDARY outcome

Timeframe: Day 1 until Day 786.

Population: The analysis was ITT. The participants are randomized children having at least one parent report.

The Caregiver Impact Questionnaire (CIQ) is a 6 item assessment addressing lack of sleep, absence from work or education, canceling of family activities, changing daily activities, feeling nervous and feeling helpless. Each of these responses is expanded to a continuous scale from 0 (no impact on caregiver) to 100 (greatest impact). The average response, i.e., score, for these 6 items is calculated. The overall caregiver's quality of life (QOL) score, also captured on the CIQ, is expressed on a ordinal response scale that ranges from 0 (worst quality of life) to 10 (best quality). The CIQ is administered to the parent every 16 weeks after randomization and occasionally at sick visits.

Outcome measures

Outcome measures
Measure	Surgical Management n=883 Number of parent reports Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=818 Number of parent reports Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Mean Scores on the 6 Item Caregiver Impact Questionnaire (CIQ) Caregiver impact questionnaire score	10.82 Score on a scale Standard Error 0.53	10.93 Score on a scale Standard Error 0.55
The Mean Scores on the 6 Item Caregiver Impact Questionnaire (CIQ) Caregiver impact questionnaire--Caregiver's overall QOL score	8.55 Score on a scale Standard Error 0.06	8.50 Score on a scale Standard Error 0.06

SECONDARY outcome

Timeframe: Day 1 until Day 786. The mean length of actual follow-up was 662 days / 1.8 years.

Population: The analysis was ITT. The participants are randomized children.

Total costs in US dollars were calculated by summing costs of lost wages, office visits, medical procedures, hospitalizations, and medications. Total QALDs were calculated by summing daily utility values. A utility value of 1.0 was assumed for days without AOM, otorrhea, or hospitalization. For days where these states were reported, published utility values associated with each state were used. To arrive at the final measure, total costs were divided by total utility values.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Total Cost of Management of Recurrent Acute Otitis Media Per Quality Adjusted Life Days (QALDs) as a Measure of Cost-Effectiveness	7.19 US dollars per quality adjusted life day	5.79 US dollars per quality adjusted life day

SECONDARY outcome

Timeframe: Day 1 until Day 786. The mean length of actual follow-up was 662 days / 1.8 years.

Population: The analysis was ITT. The participants are randomized children.

Outcome measures

Outcome measures
Measure	Surgical Management n=129 Participants Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 Participants Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
The Total Cost of Management of Recurrent Acute Otitis Media Per Quality Adjusted Life Days (QALDs) as a Measure of Cost-Effectiveness According to the Estimated Risk of Acute Otitis Media Recurrences at Enrollment Children considered at low risk of AOM recurrence	6.25 US dollars per quality adjusted life day	5.70 US dollars per quality adjusted life day
The Total Cost of Management of Recurrent Acute Otitis Media Per Quality Adjusted Life Days (QALDs) as a Measure of Cost-Effectiveness According to the Estimated Risk of Acute Otitis Media Recurrences at Enrollment Children considered at high risk of AOM recurrence	8.00 US dollars per quality adjusted life day	5.91 US dollars per quality adjusted life day

Adverse Events

Surgical Management

Serious events: 3 serious events

Other events: 98 other events

Deaths: 0 deaths

Non-Surgical Management

Serious events: 7 serious events

Other events: 70 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Surgical Management n=129 participants at risk Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 participants at risk Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
Gastrointestinal disorders Ileocolic intussusception	0.78% 1/129 • Number of events 1 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	0.00% 0/121 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Gastrointestinal disorders Gastroenteritis	0.78% 1/129 • Number of events 1 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	0.00% 0/121 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Gastrointestinal disorders Protocol-defined diarrhea	0.00% 0/129 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	0.83% 1/121 • Number of events 1 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Respiratory, thoracic and mediastinal disorders Asthma exacerbation	0.78% 1/129 • Number of events 1 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	2.5% 3/121 • Number of events 3 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Respiratory, thoracic and mediastinal disorders Bronchiolitis	0.00% 0/129 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	0.83% 1/121 • Number of events 1 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Respiratory, thoracic and mediastinal disorders Respiratory insufficiency	0.00% 0/129 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	0.83% 1/121 • Number of events 1 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Nervous system disorders Complex febrile seizure	0.00% 0/129 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	0.83% 1/121 • Number of events 1 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
General disorders Dehydration	0.00% 0/129 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	0.83% 1/121 • Number of events 1 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.

Other adverse events

Other adverse events
Measure	Surgical Management n=129 participants at risk Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops Tympanostomy tube placement: 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. Ofloxacin Otic: 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.	Non-Surgical Management n=121 participants at risk Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone Amoxicillin-Clavulanate and/or Ceftriaxone: 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.
Gastrointestinal disorders Protocol-defined Diarrhea	16.3% 21/129 • Number of events 43 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	28.1% 34/121 • Number of events 59 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Skin and subcutaneous tissue disorders Diaper dermatitis	19.4% 25/129 • Number of events 46 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	27.3% 33/121 • Number of events 56 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Ear and labyrinth disorders Tube otorrhea	72.9% 94/129 • Number of events 320 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	28.1% 34/121 • Number of events 119 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Ear and labyrinth disorders Otorrhea, not tube associated	0.00% 0/129 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	6.6% 8/121 • Number of events 8 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.
Ear and labyrinth disorders Refractory tube otorrhea	2.3% 3/129 • Number of events 4 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.	1.7% 2/121 • Number of events 2 • The occurrence of adverse events (AEs) were recorded from Day 1 (enrollment) through Day 786. Parents were interviewed at each scheduled study visit, at interim illness visits, and at the end-of-study visit to determine if their child had any adverse events since the preceding visit. All recorded AEs were followed to adequate resolution. Additionally, during periods of antimicrobial therapy for AOM, parents recorded in an electronic memory aid (or a paper memory aid if an electronic memory aid was unavailable) complete information regarding frequency and consistency of bowel movements, diaper rash necessitating administration of topical antifungal therapy, and otorrhea.

Additional Information

Alejandro Hoberman, MD

UPMC Children's Hospital of Pittsburgh

Phone: 412-999-3277

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place