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Efficacy of Short-Course Antimicrobial Treatment for Children With Acute Otitis Media and Impact on Resistance

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ClinicalTrials.gov Identifier: NCT01511107
Recruitment Status : Terminated (The primary objective of the study was met.)
First Posted : January 18, 2012
Results First Posted : February 10, 2017
Last Update Posted : October 6, 2017
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
Alejandro Hoberman, University of Pittsburgh

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Acute Otitis Media
Interventions Drug: Amoxicillin-Clavulanate, 10 days
Drug: Amoxicillin-Clavulanate, 5 days
Enrollment 520
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days. Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Period Title: Overall Study
Started 260 [1] 260 [1]
Completed 238 [2] 219 [2]
Not Completed 22 41
Reason Not Completed
Ineligible             3             2
Lost to Follow-up             10             19
Withdrawal by Subject             9             20
[1]
Randomized to the treatment group.
[2]
Completed - Assessed at a final visit in Sep or at the end of the respiratory season in Apr or May.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days Total
Hide Arm/Group Description Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days. Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10. Total of all reporting groups
Overall Number of Baseline Participants 257 258 515
Hide Baseline Analysis Population Description
520 children underwent randomization; 260 were randomized to the amoxicillin-clavulante 10 days group and 260 to the amoxicillin-clavulante 5 days, placebo 5 days group. 3 and 2, respectively, were found ineligible after randomization and were withdrawn by the PI. The remaining 257 and 258 participants, respectively, were the basis for analysis.
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
6-11 months 129 132 261
12-17 months 80 77 157
18-23 months 48 49 97
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
Female
115
  44.7%
123
  47.7%
238
  46.2%
Male
142
  55.3%
135
  52.3%
277
  53.8%
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
Hispanic or Latino
24
   9.3%
23
   8.9%
47
   9.1%
Not Hispanic or Latino
233
  90.7%
235
  91.1%
468
  90.9%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Parents were asked what ethnicity they would use to describe their child.
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
7
   2.7%
5
   1.9%
12
   2.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
110
  42.8%
118
  45.7%
228
  44.3%
White
116
  45.1%
110
  42.6%
226
  43.9%
More than one race
21
   8.2%
21
   8.1%
42
   8.2%
Unknown or Not Reported
3
   1.2%
4
   1.6%
7
   1.4%
[1]
Measure Description: Parents were asked what race or races they would use to describe their child.
Study Site   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
Children's Hospital of Pittsburgh (CHP) 163 163 326
Children's Community Pediatrics 47 47 94
Kentucky Pediatric and Adult Research 47 48 95
[1]
Measure Description: Participating clinical study sites included: Children's Hospital of Pittsburgh (CHP) of University of Pittsburgh Medical Center (UPMC) Primary Care Center - Oakland, CHP of UPMC Emergency Department, Pittsburgh, Pennsylvania (PA); its affiliated University of Pittsburgh Clinical and Translational Science Institute (PittNet) Pediatric Practice-Based Research Network (PBRN) - PittNet North, East, South, City Loop, Pittsburgh, PA and Kittanning, PA; and Kentucky Pediatric/Adult Research (KPAR) and Physicians to Children and Adolescents (PTCA) Bardstown, Kentucky (KY).
Maternal Education   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
Less than high school 31 26 57
High school graduate or equivalent 150 169 319
College graduate 76 62 138
Unknown 0 1 1
[1]
Measure Description: Parent was asked about the highest level of maternal education. High school graduate or equivalent implies the mother has graduated high school graduate or has a General Education Diploma (GED) or has attended technical school or some college or has an associates degree.
Type of Health Insurance   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
Private 84 75 159
Public 171 179 350
None 2 4 6
[1]
Measure Description: Type of health insurance relates to the child's insurance.
Exposure to Other Children   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
Not exposed 109 105 214
Exposed 148 153 301
[1]
Measure Description: Exposed to other children is defined as a being exposed to 3 or more children for 10 or more hours per week or living in a home with at least 3 other children under the age of 18.
Acute Otitis Media Severity of Symptoms (AOM-SOS) Score   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
3-5 43 59 102
6-8 75 70 145
9-11 98 95 193
12-14 41 34 75
[1]
Measure Description: The AOM-SOS scale measures seven discrete items: tugging of ears, crying, irritability, difficulty sleeping, diminished activity, diminished appetite, and fever. Parents are asked to rate these symptoms in comparison with the child’s usual state, as “none,” “a little,” or “a lot,” with corresponding scores of 0, 1, and 2. Thus, total scores range from 0 to 14, with higher scores indicating greater severity of symptoms. Children must have at least a total score of 3 at enrollment to qualify for the study.
Mean AOM-SOS Score   [1] 
Mean (Standard Deviation)
Unit of measure:  AOM-SOS score
Number Analyzed 257 participants 258 participants 515 participants
8.6  (2.9) 8.2  (3.0) 8.4  (3.0)
[1]
Measure Description: The AOM-SOS scale measures seven discrete items: tugging of ears, crying, irritability, difficulty sleeping, diminished activity, diminished appetite, and fever. Parents are asked to rate these symptoms in comparison with the child’s usual state, as “none,” “a little,” or “a lot,” with corresponding scores of 0, 1, and 2. Thus, total scores range from 0 to 14, with higher scores indicating greater severity of symptoms.
Estimated severity of illness from pain and fever history only   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
Likely nonsevere 111 121 232
Likely severe 146 137 283
[1]
Measure Description: AOM episodes were categorized as “likely severe” if the parent described the child as having had “a lot” of ear tugging or “a lot” of fever during the preceding 24 hours, else the episode was categorized as "likely nonsevere."
Laterality of Acute Otitis Media (AOM)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
Unilateral 136 126 262
Bilateral 121 132 253
Degree of Tympanic Membrane Bulging   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
Slight 35 45 80
Moderate 137 135 272
Marked 85 78 163
[1]
Measure Description: If a child has unilateral AOM, the degree of bulging reflects the degree of bulging in the ear with AOM. If a child has bilateral AOM, the degree of bulging reflects the degree of bulging in the ear with the greater level of bulging,
Streptococcus Pneumoniae (S pneumoniae) Sensitivity in Nasopharyngeal Cultures   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
S pneumoniae absent 131 120 251
S pneumoniae present, susceptible 84 94 178
S pneumoniae present, intermediate 20 28 48
S pneumoniae present, resistant 21 16 37
Unknown, no culture 1 0 1
[1]
Measure Description: Susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available , susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm.
Haemophilus Influenzae (H influenzae) Sensitivity in Nasopharyngeal Cultures   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 257 participants 258 participants 515 participants
H influenzae absent 172 197 369
H influenzae present, susceptible 53 37 90
H influenzae present, nonsusceptible 31 24 55
Unknown, no culture 1 0 1
[1]
Measure Description: Susceptible was defined as beta-lactamase-negative and E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and E test MIC >1 µg/mL.
1.Primary Outcome
Title The Distribution of Children Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit Specific to the Index Episode of AOM
Hide Description

Proportion of children initially diagnosed with AOM who experience treatment failure at or before the day 12-14 visit.

TF is defined as substantial persistence or worsening of symptoms specifically attributable to AOM, or of otoscopic signs of AOM, after 72 hours from the time of randomization, such that additional antimicrobial therapy is deemed advisable. If a parent/legal guardian is unwilling to continue the assigned study product regimen, the participant will be categorized as TF. Should a participant be administered another systemic antibiotic while taking study medication or prior to Day 16, the participant will be considered a TF. Clinical success is defined as complete or substantial resolution of symptoms specifically attributable to AOM for 48 hours and of otoscopic signs of acute inflammation (bulging of the tympanic membrane (TM) or intense erythema), with or without persistence of middle-ear effusion, such that no additional antibiotic therapy is deemed advisable.

Time Frame From 72 hours after randomization until day 21 of the index episode. The mean day for this visit was 13.2.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was intent to treat (ITT). The number of participants is equal to the number of children randomized & eligible who had a clinical assessment at or before the day 12-14 visit.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 238 229
Measure Type: Number
Unit of Measure: participants
Treatment failure 39 77
Treatment success 199 152
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments The null hypothesis that amoxicillin-clavulanate 5 days, placebo 5 days (reduced duration) is inferior to amoxicillin-clavulanate 10 days (standard duration) is tested against the alternative that reduced duration treatment is noninferior. Assuming failure rates of 15% and 25% in the standard and reduced duration groups, respectively, a 2-sided significance level of .05 and 10% attrition, it was calculated that 300 participants per group, would provide power of 95% for finding inferiority.
Type of Statistical Test Non-Inferiority or Equivalence
Comments A noninferiority margin of 10% was used. Non-inferiority can be established by placing a confidence interval on the difference in the proportion of TFs in subjects randomized to the 10 day regimen and the proportion of TFs in subjects randomized to the 5 day regimen, and determining whether the lower 95% confidence bound is greater than -10%.
Method of Estimation Estimation Parameter Difference between proportions
Estimated Value -.172
Confidence Interval (2-Sided) 95%
-.253 to -.091
Parameter Dispersion
Type: Standard Deviation
Value: .039
Estimation Comments [Not Specified]
2.Secondary Outcome
Title The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit
Hide Description

Proportion of AOM recurrences resulting in treatment failure at or before the day 12-14 visit.

TF is defined as substantial persistence or worsening of symptoms specifically attributable to AOM, or of otoscopic signs of AOM, after 72 hours from the time of the recurrence, such that additional antimicrobial therapy is deemed advisable. If a parent/legal guardian is unwilling to continue the assigned study product regimen, the participant will be categorized as TF. Should a participant be administered another systemic antibiotic while taking study medication or prior to Day 16, the participant will be considered a TF. Clinical success is defined as complete or substantial resolution of symptoms specifically attributable to AOM for 48 hours and of otoscopic signs of acute inflammation (bulging of the TM or intense erythema), with or without persistence of middle-ear effusion, such that no additional antibiotic therapy is deemed advisable.

Time Frame From 72 hours after the AOM recurrence was diagnosed until day 21 of the recurrence. The mean day for this visit was 13.3.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The number of participants is equal to the number of children randomized & eligible who had a clinical assessment at or before the day 12-14 visit following an AOM recurrence.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 101 84
Overall Number of Units Analyzed
Type of Units Analyzed: Recurrences
133 102
Measure Type: Number
Unit of Measure: recurrence
Treatment failure 25 29
Treatment success 108 73
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments A noninferiority margin of 10% was used. Non-inferiority can be established by placing a confidence interval on the difference in the proportion of TFs in subjects randomized to the 10 day regimen and the proportion of TFs in subjects randomized to the 5 day regimen, and determining whether the lower 95% confidence bound is greater than -10%.
Method of Estimation Estimation Parameter Difference between proportions
Estimated Value -.096
Confidence Interval (2-Sided) 95%
-.209 to .016
Parameter Dispersion
Type: Standard Deviation
Value: .053
Estimation Comments [Not Specified]
3.Secondary Outcome
Title The Distribution of Children With a Nasopharyngeal (NP) Culture at Enrollment That is Negative for AOM Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Hide Description AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame The day 12-14 visit. The mean day for this visit was 13.3.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having a NP culture at enrollment that is negative for both S pn and H flu and a NP culture at the day 12-14 visit which is either positive (+) for >=1 penicillin nonsusceptible pathogen OR pathogen negative (-) or + only for >=1 penicillin susceptible pathogen.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 75 72
Measure Type: Number
Unit of Measure: participants
+ for nonsusceptible pathogen(s) day 12-14 15 11
pathogen - or + only for susceptible day 12-14 60 61
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the proportion of children whose NP isolates at enrollment are negative for AOM pathogens for whom the NP culture at day 12-14 yields a nonsusceptible pathogen.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.45
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
4.Secondary Outcome
Title The Distribution of AOM Recurrences With a Nasopharyngeal (NP) Culture at Onset That is Negative for AOM Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Hide Description AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame The day 12-14 visit. The mean day for this visit was 13.4.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having a NP culture at onset that is negative for both S pn and H flu and a NP culture at the day 12-14 visit which is either positive (+) for >=1 penicillin nonsusceptible pathogen OR pathogen negative (-) or + only for >=1 penicillin susceptible pathogen.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 42 26
Overall Number of Units Analyzed
Type of Units Analyzed: Recurrences
46 32
Measure Type: Number
Unit of Measure: recurrence
+ for nonsusceptible pathogen(s) day 12-14 12 8
pathogen - or + only for susceptible day 12-14 34 24
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: For AOM recurrences with a NP culture at onset that is negative for AOM pathogens, there is no difference between the two groups regarding the proportion of NP cultures at Day 12-14 that yield a nonsusceptible pathogen.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.95
Comments [Not Specified]
Method Generalized estimating equations
Comments [Not Specified]
5.Secondary Outcome
Title The Distribution of Children With a Nasopharyngeal (NP) Culture at Enrollment That is Positive Only for One or More Susceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Hide Description AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame The day 12-14 visit. The mean day for this visit was 13.2.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having a NP culture at enrollment that is positive only for >=1 susceptible pathogen & a NP culture at the day 12-14 visit which is either positive (+) for >=1 penicillin nonsusceptible pathogen OR pathogen negative (-) or + only for >=1 penicillin susceptible pathogen.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 93 90
Measure Type: Number
Unit of Measure: participants
+ for nonsusceptible pathogen(s) day 12-14 10 12
pathogen - or + only for susceptible day 12-14 83 78
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the proportion of children whose NP isolates at enrollment are positive only for one or more susceptible pathogens for whom the NP culture at day 12-14 yields a nonsusceptible pathogen.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.59
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
6.Secondary Outcome
Title The Distribution of AOM Recurrences With a Nasopharyngeal (NP) Culture at Onset That is Positive Only for One or More Susceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Hide Description AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame The day 12-14 visit. The mean day for this visit was 13.9.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having a NP culture at onset that is positive (+) only for one or more susceptible pathogens & a NP culture at the day 12-14 visit which is either + for >=1 penicillin nonsusceptible pathogen OR pathogen negative (-) or + only for >=1 penicillin susceptible pathogen.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 39 32
Overall Number of Units Analyzed
Type of Units Analyzed: Recurrences
44 33
Measure Type: Number
Unit of Measure: recurrence
+ for nonsusceptible pathogen(s) day 12-14 8 6
pathogen - or + only for susceptible day 12-14 36 27
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: For AOM recurrences with a NP culture at onset that is positive only for one or more susceptible pathogens, there is no difference between the two groups regarding the proportion of NP cultures at Day 12-14 that yield a nonsusceptible pathogen.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.99
Comments [Not Specified]
Method Generalized estimating equations
Comments [Not Specified]
7.Secondary Outcome
Title The Distribution of Children With a Nasopharyngeal (NP) Culture at Enrollment That is Positive for One or More Nonsusceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Hide Description AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame The end-of-treatment visit. The mean day for this visit was 13.6.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having both a NP culture at enrollment that is positive (+) for one or more nonsusceptible pathogens & a NP culture at the day 12-14 visit which is either + for >=1 penicillin nonsusceptible pathogen OR pathogen negative (-) or + only for >=1 penicillin susceptible pathogen.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 64 60
Measure Type: Number
Unit of Measure: participants
+ for nonsusceptible pathogen(s) day 12-14 34 28
pathogen - or + only for susceptible day 12-14 30 32
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the proportion of children whose NP isolates at enrollment are positive for one or more nonsusceptible pathogens for whom the NP culture at day 12-14 yields a nonsusceptible pathogen.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.47
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
8.Secondary Outcome
Title The Distribution of AOM Recurrences With a Nasopharyngeal (NP) Culture at Onset That is Positive for One or More Nonsusceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Hide Description AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame The end-of-treatment visit. The mean day for this visit was 13.4.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having a NP culture at onset that is positive (+) for >=1 nonsusceptible pathogen & a NP culture at the day 12-14 visit which is either + for >=1 penicillin nonsusceptible pathogen OR pathogen negative (-) or + only for >=1 penicillin susceptible pathogen.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 29 27
Overall Number of Units Analyzed
Type of Units Analyzed: Recurrences
33 29
Measure Type: Number
Unit of Measure: recurrence
+ for nonsusceptible pathogen(s) day 12-14 17 22
pathogen - or + only for susceptible day 12-14 16 7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: For AOM recurrences with a NP culture at onset that is positive for one or more nonsusceptible pathogens, there is no difference between the two groups regarding the proportion of NP cultures at Day 12-14 that yield a nonsusceptible pathogen.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments [Not Specified]
Method Generalized estimating equations
Comments [Not Specified]
9.Secondary Outcome
Title The Distribution of Children Whose Nasopharyngeal (NP) Isolates at Enrollment Are Pathogen Negative or Positive Only for at Least One Susceptible Pathogen Who Become Colonized With Nonsusceptible Pathogens at Any Time Over the Course of Follow-up
Hide Description AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame Day 1 of study entry until day 365
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having both a NP culture at enrollment that is either pathogen negative or positive only for >=1 susceptible pathogen and a NP culture at some time over the course of followup.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 181 177
Measure Type: Number
Unit of Measure: participants
+ for a nonsusceptible pathogen during followup 85 78
- for a nonsusceptible pathogen during followup 96 99
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference in the proportion of subjects whose NP isolates at enrollment are pathogen-negative or positive only for at least one susceptible pathogen who become colonized with penicillin non-susceptible pathogens at any time over the course of follow-up
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.58
Comments [Not Specified]
Method Regression, Logistic
Comments The p-value is adjusted for the culture result at enrollment.
10.Secondary Outcome
Title The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered
Hide Description AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children with at least one follow-up, nonillness visit, with a nasopharyngeal (NP) culture which is either positive (+) for >=1 penicillin nonsusceptible pathogens or positive (+) only for >=1 penicillin susceptible pathogens or pathogen negative (-).
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 211 189
Overall Number of Units Analyzed
Type of Units Analyzed: Visits
415 359
Measure Type: Number
Unit of Measure: Visit
+ for nonsusceptible pathogen(s) 79 64
pathogen - or + only for susceptible pathogen(s) 336 295
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference in the proportion of 6 week follow-up, non-illness visits at which a penicillin-nonsusceptible pathogen is recovered.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.74
Comments [Not Specified]
Method Generalized estimating equations
Comments [Not Specified]
11.Secondary Outcome
Title The Distribution of Children for Whom the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit, Specific to the Index Episode, Yields a Nonsusceptible Streptococcus Pneumoniae (S pn) Isolate
Hide Description In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm.
Time Frame The day 12-14 visit specific to the index episode. The mean day for this visit was 13.4.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The number of participants is equal to the number of children randomized & eligible having a NP culture at the day 12-14 visit following the index episode.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 233 222
Measure Type: Number
Unit of Measure: participants
S pn, nonsusceptible 23 26
S pn, susceptible 5 10
S pn, absent 205 186
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups regarding the proportion of NP cultures at Day 12-14 that yield a nonsusceptible S pn isolate.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.72
Comments [Not Specified]
Method Regression, Logistic
Comments The p-value is adjusted for S pn susceptibility at the index episode.
12.Secondary Outcome
Title The Distribution of AOM Recurrences for Which the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit Yields a Nonsusceptible Streptococcus Pneumoniae (S pn) Isolate
Hide Description In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm.
Time Frame The day 12-14 visit following a recurrence. The mean day for this visit was 13.6.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The number of participants is equal to the number of children randomized & eligible having a NP culture at the day 12-14 visit following an AOM recurrence.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 100 82
Overall Number of Units Analyzed
Type of Units Analyzed: Recurrences
131 99
Measure Type: Number
Unit of Measure: recurrence
S pn, nonsusceptible 20 25
S pn, susceptible 4 6
S pn, absent 107 68
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments [Not Specified]
Method Generalized estimating equations
Comments The p-value is adjusted for S pn susceptibility at onset of the AOM recurrence.
13.Secondary Outcome
Title The Distribution of Children for Whom the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit, Specific to the Index Episode, Yields a Nonsusceptible Haemophilus Influenzae (H Flu) Isolate
Hide Description In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame The day 12-14 visit specific to the index episode. The mean day for this visit was 13.4.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The number of participants is equal to the number of children randomized & eligible having a NP culture at the day 12-14 visit following the index episode.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 233 222
Measure Type: Number
Unit of Measure: participants
H flu, nonsusceptible 38 28
H flu, susceptible 39 37
H flu, absent 156 157
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups regarding the proportion of NP cultures at Day 12-14 that yield a nonsusceptible H flu isolate.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.47
Comments [Not Specified]
Method Regression, Logistic
Comments The p-value is adjusted for H flu susceptibility at onset of the index episode.
14.Secondary Outcome
Title The Distribution of AOM Recurrences for Which the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit Yields a Nonsusceptible Haemophilus Influenzae (H Flu) Isolate
Hide Description In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame The day 12-14 visit following a recurrence. The mean day for this visit was 13.6.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The number of participants is equal to the number of children randomized & eligible having a NP culture at the day 12-14 visit following an AOM recurrence.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 100 82
Overall Number of Units Analyzed
Type of Units Analyzed: Recurrences
131 99
Measure Type: Number
Unit of Measure: recurrence
H flu, nonsusceptible 19 15
H flu, susceptible 17 20
H flu, absent 95 64
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.69
Comments [Not Specified]
Method Generalized estimating equations
Comments The p-value is adjusted for H flu susceptibility at onset of the AOM recurrence.
15.Secondary Outcome
Title The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment
Hide Description An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences.
Time Frame Day 1 of study entry until day 60.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having follow-up greater than or equal to day 60.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 241 224
Measure Type: Number
Unit of Measure: participants
# cumulative recurrences/relapses = 0 173 173
# cumulative recurrences/relapses = 1 66 48
# cumulative recurrences/relapses = 2 2 3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the proportion of children followed greater than 60 days having at least one AOM relapse or recurrence within 60 days of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.16
Comments [Not Specified]
Method Regression, Logistic
Comments The p-value is adjusted for site & the stratification variables, namely age group & exposure or nonexposure to ≥3 children for ≥10 hours per week.
16.Secondary Outcome
Title The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season
Hide Description An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences.
Time Frame Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children completing the study.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 238 219
Measure Type: Number
Unit of Measure: participants
# cumulative recurrences/relapses = 0 135 133
# cumulative recurrences/relapses = 1 61 59
# cumulative recurrences/relapses = 2 31 20
# cumulative recurrences/relapses = 3 8 4
# cumulative recurrences/relapses = 4 3 3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the proportion of children completing the study having at least one AOM relapse or recurrence within the entire respiratory season.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.32
Comments [Not Specified]
Method Regression, Logistic
Comments The p-value is adjusted for site & the stratification variables, namely age group & exposure or nonexposure to ≥3 children for ≥10 hours per week.
17.Secondary Outcome
Title The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within 60 Days of Enrollment
Hide Description

An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences.

The rate, expressed as a monthly rate, is calculated by dividing the total number of recurrences and relapses within 60 days of enrollment by the number of months of follow-up within 60 days of enrollment.

Time Frame Day 1 of study entry until day 60.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having follow-up beyond day 16.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 245 232
Mean (Standard Deviation)
Unit of Measure: recurrences/relapses per month
0.15  (0.24) 0.12  (0.23)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the rate of recurrences/relapses within 60 days of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.23
Comments [Not Specified]
Method Regression, Poisson
Comments The p-value is adjusted for site & the stratification variables, namely age group & exposure or nonexposure to ≥3 children for ≥10 hours per week.
18.Secondary Outcome
Title The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within the Entire Respiratory Season
Hide Description

An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences.

The rate, expressed as a monthly rate, is calculated by dividing the total number of recurrences and relapses by the number of months of follow-up.

Time Frame Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The participants are randomized & eligible children having follow-up beyond day 16.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 245 232
Mean (Standard Deviation)
Unit of Measure: recurrences/relapses per months followed
0.14  (0.18) 0.12  (0.19)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the rate of recurrences/relapses within the entire respiratory season.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.22
Comments [Not Specified]
Method Regression, Poisson
Comments The p-value is adjusted for site & the stratification variables, namely age group & exposure or nonexposure to ≥3 children for ≥10 hours per week.
19.Secondary Outcome
Title The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season
Hide Description Systemic antibiotics include the study product, Amoxicillin-Clavulanate, dispensed for either 10 or 5 days and various concomitant medications, i.e. Amoxicillin, Amox/Clav, Azithromycin, Cefdinir, Cefpodoxime, Ceftriaxone, Erythromycin, Trimethoprim-Sulfamethoxazole, Omnicef, Augmentin, Azithromycin, Cefazolin, Clarythromycin and Ciprofloxacin.
Time Frame Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The number of participants is equal to the number of children randomized & eligible.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 257 258
Mean (Standard Deviation)
Unit of Measure: days
Study product 14.72  (6.77) 6.79  (3.01)
Other systemic antibiotic 6.19  (9.33) 7.98  (10.94)
All systemic antibiotics 20.91  (12.70) 14.77  (12.10)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the mean number of days a systemic antibiotic was received during the respiratory season.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments [Not Specified]
Method Regression, Linear
Comments The p-value is adjusted for site & the stratification variables and for length of follow-up.
20.Secondary Outcome
Title The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14
Hide Description The AOM-SOS scale measures seven discrete items: tugging of ears, crying, irritability, difficulty sleeping, diminished activity, diminished appetite, and fever. The parent rated each of these symptoms in comparison with the child's usual state, as "none," "a little," or "a lot," with corresponding scores of 0, 1, and 2, and recorded the ratings in a diary. Each set of ratings was summed to obtain an AOM-SOS score as a measure of symptom burden. Total scores range from 0 to 14, with higher scores indicating greater severity of symptoms. For instances in which the participant was declared a treatment failure, scores are included up to, but not including the day of the failure. Otherwise, scores day 6 to day 14 are included.
Time Frame From day 6 of administration of study product until day 14 for all episodes
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The number of participants equals the number of children with at least one AOM-SOS score from day 6 of administration of study product to day 14. The scores were based on diaries completed at home by the child's parent.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 234 230
Mean (Standard Deviation)
Unit of Measure: AOM-SOS score
Day 6 1.72  (2.14) 1.64  (2.38)
Day 7 1.46  (2.11) 1.57  (2.53)
Day 8 1.29  (1.99) 1.56  (2.38)
Day 9 1.29  (2.10) 1.41  (2.22)
Day 10 1.12  (1.96) 1.43  (2.36)
Day 11 1.02  (1.84) 1.40  (2.27)
Day 12 1.07  (1.83) 1.25  (2.12)
Day 13 1.15  (1.97) 1.40  (2.47)
Day 14 1.16  (1.93) 1.37  (2.39)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups regarding the symptom burden as measured by the respective mean scores over time.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.07
Comments [Not Specified]
Method Generalized estimating equations
Comments The p-value is adjusted for site & the stratification variables, episode, day of the diary and AOM-SOS score at the episode.
21.Secondary Outcome
Title The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product
Hide Description Protocol-defined diarrhea is defined as the occurrence of three or more watery stools in 1 day or two watery stools daily for 2 consecutive days and is limited to events associated with study product.
Time Frame Day 1 of administration of study product until day 16 for all episodes
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis was ITT. The number of participants equals the number of children randomized and eligible.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 257 258
Measure Type: Number
Unit of Measure: participants
PDD reported 78 75
PDD not reported 179 183
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the proportion of children for whom PDD was reported.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.70
Comments [Not Specified]
Method Regression, Logistic
Comments The p-value is adjusted for site & the stratification variables, namely age group & exposure or nonexposure to ≥3 children for ≥10 hours per week.
22.Secondary Outcome
Title The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product
Hide Description Diaper dermatitis is defined as dermatitis in the diaper area calling for prescription of a topical antifungal agent and is limited to events associated with study product.
Time Frame Day 1 of administration of study product until day 16 for all episodes
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Hide Analysis Population Description
The analysis was ITT. The number of participants equals the number of children randomized and eligible.
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description:
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days.
Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
Overall Number of Participants Analyzed 257 258
Measure Type: Number
Unit of Measure: participants
Diaper dermatitis reported 85 87
Diaper dermatitis not reported 172 171
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Statistical Analysis Overview Comparison Group Selection Amoxicillin-Clavulanate, 10 Days, Amoxicillin-Clavulanate, 5 Days
Comments Null hypothesis: There is no difference between the two groups in the proportion of children for whom diaper dermatitis was reported.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.86
Comments [Not Specified]
Method Regression, Logistic
Comments The p-value is adjusted for site & the stratification variables, namely age group & exposure or nonexposure to ≥3 children for ≥10 hours per week.
Time Frame Parents were interviewed at each scheduled study visit (Day 1, Day 12-14, Day 16-30, 6 week), at the Day 4-6 phone call, at interim illness visits through May 31st, and at the final September visit to determine if their child had any adverse events.
Adverse Event Reporting Description Staff reviewed child's medical records since their last study visit for any adverse events (AEs). A medical condition that was present at the time that the child was screened was considered baseline and not reported as an AE. If the severity of any pre-existing medical condition increased at any time during the study, it was reported as an AE.
 
Arm/Group Title Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Hide Arm/Group Description Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days. Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for Days 1-5 followed by placebo in 2 divided doses for Days 6-10.
All-Cause Mortality
Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/257 (1.17%)      5/258 (1.94%)    
Gastrointestinal disorders     
Gastroenteritis  1  1/257 (0.39%)  1 1/258 (0.39%)  1
General disorders     
Dehydration  1  0/257 (0.00%)  0 1/258 (0.39%)  1
Fever of unknown origin  1  1/257 (0.39%)  1 0/258 (0.00%)  0
Infections and infestations     
Wound infection  1  0/257 (0.00%)  0 1/258 (0.39%)  1
Nervous system disorders     
Seizure  1  0/257 (0.00%)  0 1/258 (0.39%)  1
Respiratory, thoracic and mediastinal disorders     
Asthma  1  1/257 (0.39%)  1 0/258 (0.00%)  0
Bronchiolitis  1  0/257 (0.00%)  0 1/258 (0.39%)  1
Croup  1  0/257 (0.00%)  0 1/258 (0.39%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, NIH Toxicity Tables
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 4%
Amoxicillin-Clavulanate, 10 Days Amoxicillin-Clavulanate, 5 Days
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   240/257 (93.39%)      242/258 (93.80%)    
Ear and labyrinth disorders     
Non-protocol acute otitis media (AOM)  1 [1]  44/257 (17.12%)  48 48/258 (18.60%)  60
Gastrointestinal disorders     
Gastroenteritis  1  29/257 (11.28%)  31 27/258 (10.47%)  28
Protocol defined diarrhea  1 [2]  84/257 (32.68%)  112 91/258 (35.27%)  105
Vomiting  1  54/257 (21.01%)  62 51/258 (19.77%)  61
General disorders     
Fever  1  44/257 (17.12%)  58 42/258 (16.28%)  45
Viral illness  1  30/257 (11.67%)  32 25/258 (9.69%)  29
Infections and infestations     
Conjunctivitis  1  37/257 (14.40%)  40 36/258 (13.95%)  37
Sinusitis  1  12/257 (4.67%)  12 8/258 (3.10%)  9
Respiratory, thoracic and mediastinal disorders     
Bronchospasm, acute  1 [3]  48/257 (18.68%)  65 47/258 (18.22%)  58
Upper respiratory infection  1  197/257 (76.65%)  469 191/258 (74.03%)  432
Skin and subcutaneous tissue disorders     
Diaper dermatitis  1  166/257 (64.59%)  300 155/258 (60.08%)  243
Rash  1 [4]  27/257 (10.51%)  30 17/258 (6.59%)  17
Viral exanthem  1  21/257 (8.17%)  22 24/258 (9.30%)  30
Surgical and medical procedures     
Tympanostomy tube placement  1  19/257 (7.39%)  19 22/258 (8.53%)  22
Indicates events were collected by systematic assessment
1
Term from vocabulary, NIH Toxicity Tables
[1]
Non-protocol AOM refers to AOM diagnosed by a non-protocol provider and not confirmed by a protocol provider.
[2]
Protocol defined diarrhea is defined as 3 watery stools in 1 day or 2 watery stools for each of 2 consecutive days.
[3]
This includes transient episodes of bronchospasm that did not require treatment, as seen in bronchiolitis.
[4]
Rash is defined as urticaria or morbilliform or papular rash.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Alejandro Hoberman
Organization: Children's Hospital of Pittsburgh of UPMC
Phone: 412-692-5249
Responsible Party: Alejandro Hoberman, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01511107     History of Changes
Other Study ID Numbers: 10-0083
AI2009058 ( Other Identifier: NIH NIAID )
First Submitted: January 10, 2012
First Posted: January 18, 2012
Results First Submitted: September 30, 2016
Results First Posted: February 10, 2017
Last Update Posted: October 6, 2017