Acute Otitis Media
Conditions
Keywords
acute otitis media, ear infection, antimicrobial therapy, antimicrobial resistance
Brief summary
The investigators will study whether, in young children with acute otitis media (AOM), shortening length of antibiotic treatment as a strategy for reducing antimicrobial resistance provides satisfactory clinical outcome. This is a Phase 2b multicenter, randomized, double-blind, placebo-controlled clinical trial in 600 children aged 6 through 23 months comparing the efficacy of consistent reduced-duration antimicrobial treatment (5 days) with that of consistent standard-duration treatment (10 days) for each episode of AOM developing during a single respiratory season (October 1 through May 31).
Detailed description
Eligible subjects will be randomized at the enrollment visit and will have a telephone call in the course of therapy, and a subsequent visit at the end of therapy. Thereafter, they will be followed through the end of the respiratory season, and their parents will be encouraged to bring their child when concerned about a potential recurrence of AOM. At each recurrence subjects will receive the treatment regimen (either standard- or reduced-duration) to which they were randomized at study entry (consistent treatment strategy). The recruitment of eligible children with AOM of varying degrees of severity from various primary care practices in 2 separate geographic regions, i.e. Western Pennsylvania and Kentucky, representing urban, suburban and rural demographics will enhance generalizability of study findings and encourage translation to clinical practice.
Interventions
DRUGAmoxicillin-Clavulanate, 10 days
Amoxicillin-clavulanate (90/6.4mg/kg/day in 2 divided doses) Days 1-10
DRUGAmoxicillin-Clavulanate, 5 days
Amoxicillin-clavulanate (90/6.4mg/kg/day in 2 divided doses) Days 1-5 Plus Placebo Days 6-10
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Alejandro Hoberman
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 23 Months
Healthy volunteers
No
Inclusion criteria
1. Aged 6 through 23 months 2. Have evidence of AOM defined as: * recent (within 48 hours) onset of signs and symptoms as described in the Acute Otitis Media - Severity of Symptoms (AOM-SOS) Scale AND a score of ≥3 at the time of enrollment on the AOM-SOS scale * middle ear effusion evidenced by the presence of at least 2 of the following: * decreased or absent mobility of the tympanic membrane * yellow or white discoloration of the tympanic membrane * opacification of the tympanic membrane AND * acute inflammation evidenced by one of the following: * 1+ bulging of the tympanic membrane with either intense erythema or otalgia * 2+ or 3+ bulging of the tympanic membrane 3. Has received at least 2 doses of pneumococcal conjugate vaccine 4. Parent has provided informed consent
Exclusion criteria
1. Toxic appearance \[capillary refill \>3 seconds, systolic blood pressure \<60 mm Hg\]; 2. Inpatient hospitalization 3. Clinical or anatomical characteristics that might obscure response to treatment (tympanostomy tubes in place, cleft palate, or Down syndrome) 4. Sensorineural hearing loss (unilateral or bilateral) 5. Serious underlying systemic problems that might obscure response to infection (cystic fibrosis, neoplasm, juvenile diabetes) 6. Concomitant infection that would preclude evaluation of the response of the child's AOM to study product (pneumonia, periorbital cellulitis) 7. Acute wheezing exacerbation which may require treatment with systemic corticosteroids 8. Known renal or hepatic dysfunction or insufficiency 9. History of amoxicillin-clavulanate-associated cholestatic jaundice 10. Immune dysfunction or receipt of immunosuppressive therapy; chronic gastrointestinal conditions (i.e., malabsorption, inflammatory bowel disease) 11. Co-medications (systemic corticosteroids, more than one dose of systemic antimicrobial therapy within 96 hours, receipt of any investigational drug or vaccine within 30 days) 12. Hypersensitivity to penicillin, amoxicillin or amoxicillin-clavulanate, or phenylketonuria or known hypersensitivity to aspartame 13. Unable to complete study, or no access to phone 14. Previously enrolled in this study or currently enrolled in another study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | From 72 hours after randomization until day 21 of the index episode. The mean day for this visit was 13.2. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | The day 12-14 visit. The mean day for this visit was 13.3. | 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. |
| 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 | The day 12-14 visit. The mean day for this visit was 13.4. | 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. |
| 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 | The day 12-14 visit. The mean day for this visit was 13.2. | 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. |
| 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 | The day 12-14 visit. The mean day for this visit was 13.9. | 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. |
| 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 | The end-of-treatment visit. The mean day for this visit was 13.6. | 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. |
| 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 | The end-of-treatment visit. The mean day for this visit was 13.4. | 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. |
| 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 | Day 1 of study entry until day 365 | 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. |
| The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered | Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive. | 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. |
| 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 | The day 12-14 visit specific to the index episode. The mean day for this visit was 13.4. | 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. |
| 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 | The day 12-14 visit following a recurrence. The mean day for this visit was 13.6. | 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. |
| The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit | From 72 hours after the AOM recurrence was diagnosed until day 21 of the recurrence. The mean day for this visit was 13.3. | 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. |
| 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 | The day 12-14 visit following a recurrence. The mean day for this visit was 13.6. | 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. |
| The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment | Day 1 of study entry until day 60. | 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 Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive. | 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 Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within 60 Days of Enrollment | Day 1 of study entry until day 60. | 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. |
| The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within the Entire Respiratory Season | Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive. | 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. |
| The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season | Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive. | 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. |
| The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | From day 6 of administration of study product until day 14 for all episodes | 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. |
| The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product | Day 1 of administration of study product until day 16 for all episodes | 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. |
| The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product | Day 1 of administration of study product until day 16 for all episodes | 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. |
| 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 | The day 12-14 visit specific to the index episode. The mean day for this visit was 13.4. | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Amoxicillin-Clavulanate, 10 Days Amoxicillin-clavulanate administered at a dosage of 90/6.4mg/kg/day in 2 divided doses for 10 days. | 257 |
| Amoxicillin-Clavulanate, 5 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. | 258 |
| Total | 515 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible | 3 | 2 |
| Overall Study | Lost to Follow-up | 10 | 19 |
| Overall Study | Withdrawal by Subject | 9 | 20 |
Baseline characteristics
| Characteristic | Amoxicillin-Clavulanate, 10 Days | Total | Amoxicillin-Clavulanate, 5 Days |
|---|---|---|---|
| Acute Otitis Media Severity of Symptoms (AOM-SOS) Score 12-14 | 41 participants | 75 participants | 34 participants |
| Acute Otitis Media Severity of Symptoms (AOM-SOS) Score 3-5 | 43 participants | 102 participants | 59 participants |
| Acute Otitis Media Severity of Symptoms (AOM-SOS) Score 6-8 | 75 participants | 145 participants | 70 participants |
| Acute Otitis Media Severity of Symptoms (AOM-SOS) Score 9-11 | 98 participants | 193 participants | 95 participants |
| Age, Customized 12-17 months | 80 participants | 157 participants | 77 participants |
| Age, Customized 18-23 months | 48 participants | 97 participants | 49 participants |
| Age, Customized 6-11 months | 129 participants | 261 participants | 132 participants |
| Degree of Tympanic Membrane Bulging Marked | 85 participants | 163 participants | 78 participants |
| Degree of Tympanic Membrane Bulging Moderate | 137 participants | 272 participants | 135 participants |
| Degree of Tympanic Membrane Bulging Slight | 35 participants | 80 participants | 45 participants |
| Estimated severity of illness from pain and fever history only Likely nonsevere | 111 participants | 232 participants | 121 participants |
| Estimated severity of illness from pain and fever history only Likely severe | 146 participants | 283 participants | 137 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 47 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 233 Participants | 468 Participants | 235 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Exposure to Other Children Exposed | 148 participants | 301 participants | 153 participants |
| Exposure to Other Children Not exposed | 109 participants | 214 participants | 105 participants |
| Haemophilus Influenzae (H influenzae) Sensitivity in Nasopharyngeal Cultures H influenzae absent | 172 participants | 369 participants | 197 participants |
| Haemophilus Influenzae (H influenzae) Sensitivity in Nasopharyngeal Cultures H influenzae present, nonsusceptible | 31 participants | 55 participants | 24 participants |
| Haemophilus Influenzae (H influenzae) Sensitivity in Nasopharyngeal Cultures H influenzae present, susceptible | 53 participants | 90 participants | 37 participants |
| Haemophilus Influenzae (H influenzae) Sensitivity in Nasopharyngeal Cultures Unknown, no culture | 1 participants | 1 participants | 0 participants |
| Laterality of Acute Otitis Media (AOM) Bilateral | 121 participants | 253 participants | 132 participants |
| Laterality of Acute Otitis Media (AOM) Unilateral | 136 participants | 262 participants | 126 participants |
| Maternal Education College graduate | 76 participants | 138 participants | 62 participants |
| Maternal Education High school graduate or equivalent | 150 participants | 319 participants | 169 participants |
| Maternal Education Less than high school | 31 participants | 57 participants | 26 participants |
| Maternal Education Unknown | 0 participants | 1 participants | 1 participants |
| Mean AOM-SOS Score | 8.6 AOM-SOS score STANDARD_DEVIATION 2.9 | 8.4 AOM-SOS score STANDARD_DEVIATION 3 | 8.2 AOM-SOS score STANDARD_DEVIATION 3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 12 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 110 Participants | 228 Participants | 118 Participants |
| Race (NIH/OMB) More than one race | 21 Participants | 42 Participants | 21 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) White | 116 Participants | 226 Participants | 110 Participants |
| Sex: Female, Male Female | 115 Participants | 238 Participants | 123 Participants |
| Sex: Female, Male Male | 142 Participants | 277 Participants | 135 Participants |
| Streptococcus Pneumoniae (S pneumoniae) Sensitivity in Nasopharyngeal Cultures S pneumoniae absent | 131 participants | 251 participants | 120 participants |
| Streptococcus Pneumoniae (S pneumoniae) Sensitivity in Nasopharyngeal Cultures S pneumoniae present, intermediate | 20 participants | 48 participants | 28 participants |
| Streptococcus Pneumoniae (S pneumoniae) Sensitivity in Nasopharyngeal Cultures S pneumoniae present, resistant | 21 participants | 37 participants | 16 participants |
| Streptococcus Pneumoniae (S pneumoniae) Sensitivity in Nasopharyngeal Cultures S pneumoniae present, susceptible | 84 participants | 178 participants | 94 participants |
| Streptococcus Pneumoniae (S pneumoniae) Sensitivity in Nasopharyngeal Cultures Unknown, no culture | 1 participants | 1 participants | 0 participants |
| Study Site Children's Community Pediatrics | 47 participants | 94 participants | 47 participants |
| Study Site Children's Hospital of Pittsburgh (CHP) | 163 participants | 326 participants | 163 participants |
| Study Site Kentucky Pediatric and Adult Research | 47 participants | 95 participants | 48 participants |
| Type of Health Insurance None | 2 participants | 6 participants | 4 participants |
| Type of Health Insurance Private | 84 participants | 159 participants | 75 participants |
| Type of Health Insurance Public | 171 participants | 350 participants | 179 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 240 / 257 | 242 / 258 |
| serious Total, serious adverse events | 3 / 257 | 5 / 258 |
Outcome results
Primary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | Treatment failure | 39 participants |
| Amoxicillin-Clavulanate, 10 Days | 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 | Treatment success | 199 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | Treatment failure | 77 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | Treatment success | 152 participants |
Comparison: 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.95% CI: [-0.253, -0.091]
Secondary
The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered | + for nonsusceptible pathogen(s) | 79 Visit |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered | pathogen - or + only for susceptible pathogen(s) | 336 Visit |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered | + for nonsusceptible pathogen(s) | 64 Visit |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered | pathogen - or + only for susceptible pathogen(s) | 295 Visit |
Comparison: 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.p-value: 0.74Generalized estimating equations
Secondary
The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit | Treatment failure | 25 recurrence |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit | Treatment success | 108 recurrence |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit | Treatment success | 73 recurrence |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit | Treatment failure | 29 recurrence |
95% CI: [-0.209, 0.016]
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | H flu, nonsusceptible | 19 recurrence |
| Amoxicillin-Clavulanate, 10 Days | 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 | H flu, susceptible | 17 recurrence |
| Amoxicillin-Clavulanate, 10 Days | 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 | H flu, absent | 95 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | H flu, nonsusceptible | 15 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | H flu, susceptible | 20 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | H flu, absent | 64 recurrence |
p-value: 0.69Generalized estimating equations
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | S pn, nonsusceptible | 20 recurrence |
| Amoxicillin-Clavulanate, 10 Days | 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 | S pn, susceptible | 4 recurrence |
| Amoxicillin-Clavulanate, 10 Days | 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 | S pn, absent | 107 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | S pn, nonsusceptible | 25 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | S pn, susceptible | 6 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | S pn, absent | 68 recurrence |
p-value: 0.05Generalized estimating equations
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 12 recurrence |
| Amoxicillin-Clavulanate, 10 Days | 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 | pathogen - or + only for susceptible day 12-14 | 34 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 8 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | pathogen - or + only for susceptible day 12-14 | 24 recurrence |
Comparison: 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.p-value: 0.95Generalized estimating equations
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 17 recurrence |
| Amoxicillin-Clavulanate, 10 Days | 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 | pathogen - or + only for susceptible day 12-14 | 16 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | pathogen - or + only for susceptible day 12-14 | 7 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 22 recurrence |
Comparison: 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.p-value: 0.05Generalized estimating equations
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 8 recurrence |
| Amoxicillin-Clavulanate, 10 Days | 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 | pathogen - or + only for susceptible day 12-14 | 36 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 6 recurrence |
| Amoxicillin-Clavulanate, 5 Days | 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 | pathogen - or + only for susceptible day 12-14 | 27 recurrence |
Comparison: 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.p-value: >0.99Generalized estimating equations
Secondary
The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product
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
Population: The analysis was ITT. The number of participants equals the number of children randomized and eligible.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product | Diaper dermatitis reported | 85 participants |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product | Diaper dermatitis not reported | 172 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product | Diaper dermatitis reported | 87 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product | Diaper dermatitis not reported | 171 participants |
Comparison: Null hypothesis: There is no difference between the two groups in the proportion of children for whom diaper dermatitis was reported.p-value: 0.86Regression, Logistic
Secondary
The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product
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
Population: The analysis was ITT. The number of participants equals the number of children randomized and eligible.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product | PDD reported | 78 participants |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product | PDD not reported | 179 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product | PDD not reported | 183 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product | PDD reported | 75 participants |
Comparison: Null hypothesis: There is no difference between the two groups in the proportion of children for whom PDD was reported.p-value: 0.7Regression, Logistic
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | H flu, nonsusceptible | 38 participants |
| Amoxicillin-Clavulanate, 10 Days | 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 | H flu, susceptible | 39 participants |
| Amoxicillin-Clavulanate, 10 Days | 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 | H flu, absent | 156 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | H flu, absent | 157 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | H flu, nonsusceptible | 28 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | H flu, susceptible | 37 participants |
Comparison: 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.p-value: 0.47Regression, Logistic
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | S pn, nonsusceptible | 23 participants |
| Amoxicillin-Clavulanate, 10 Days | 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 | S pn, susceptible | 5 participants |
| Amoxicillin-Clavulanate, 10 Days | 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 | S pn, absent | 205 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | S pn, susceptible | 10 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | S pn, nonsusceptible | 26 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | S pn, absent | 186 participants |
Comparison: 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.p-value: 0.72Regression, Logistic
Secondary
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
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | + for a nonsusceptible pathogen during followup | 85 participants |
| Amoxicillin-Clavulanate, 10 Days | 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 | - for a nonsusceptible pathogen during followup | 96 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | - for a nonsusceptible pathogen during followup | 99 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | + for a nonsusceptible pathogen during followup | 78 participants |
Comparison: 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-upp-value: 0.58Regression, Logistic
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 15 participants |
| Amoxicillin-Clavulanate, 10 Days | 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 | pathogen - or + only for susceptible day 12-14 | 60 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 11 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | pathogen - or + only for susceptible day 12-14 | 61 participants |
Comparison: 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.p-value: 0.45Regression, Logistic
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 34 participants |
| Amoxicillin-Clavulanate, 10 Days | 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 | pathogen - or + only for susceptible day 12-14 | 30 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | pathogen - or + only for susceptible day 12-14 | 32 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 28 participants |
Comparison: 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.p-value: 0.47Regression, Logistic
Secondary
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
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.
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 10 participants |
| Amoxicillin-Clavulanate, 10 Days | 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 | pathogen - or + only for susceptible day 12-14 | 83 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | + for nonsusceptible pathogen(s) day 12-14 | 12 participants |
| Amoxicillin-Clavulanate, 5 Days | 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 | pathogen - or + only for susceptible day 12-14 | 78 participants |
Comparison: 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.p-value: 0.59Regression, Logistic
Secondary
The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment
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.
Population: The analysis was ITT. The participants are randomized \& eligible children having follow-up greater than or equal to day 60.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment | # cumulative recurrences/relapses = 0 | 173 participants |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment | # cumulative recurrences/relapses = 1 | 66 participants |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment | # cumulative recurrences/relapses = 2 | 2 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment | # cumulative recurrences/relapses = 0 | 173 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment | # cumulative recurrences/relapses = 1 | 48 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment | # cumulative recurrences/relapses = 2 | 3 participants |
Comparison: 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.p-value: 0.16Regression, Logistic
Secondary
The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season
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.
Population: The analysis was ITT. The participants are randomized \& eligible children completing the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 1 | 61 participants |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 4 | 3 participants |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 2 | 31 participants |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 3 | 8 participants |
| Amoxicillin-Clavulanate, 10 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 0 | 135 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 3 | 4 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 0 | 133 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 1 | 59 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 2 | 20 participants |
| Amoxicillin-Clavulanate, 5 Days | The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season | # cumulative recurrences/relapses = 4 | 3 participants |
Comparison: 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.p-value: 0.32Regression, Logistic
Secondary
The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 11 | 1.02 AOM-SOS score | Standard Deviation 1.84 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 9 | 1.29 AOM-SOS score | Standard Deviation 2.1 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 7 | 1.46 AOM-SOS score | Standard Deviation 2.11 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 10 | 1.12 AOM-SOS score | Standard Deviation 1.96 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 14 | 1.16 AOM-SOS score | Standard Deviation 1.93 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 8 | 1.29 AOM-SOS score | Standard Deviation 1.99 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 12 | 1.07 AOM-SOS score | Standard Deviation 1.83 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 13 | 1.15 AOM-SOS score | Standard Deviation 1.97 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 6 | 1.72 AOM-SOS score | Standard Deviation 2.14 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 14 | 1.37 AOM-SOS score | Standard Deviation 2.39 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 12 | 1.25 AOM-SOS score | Standard Deviation 2.12 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 13 | 1.40 AOM-SOS score | Standard Deviation 2.47 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 6 | 1.64 AOM-SOS score | Standard Deviation 2.38 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 7 | 1.57 AOM-SOS score | Standard Deviation 2.53 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 8 | 1.56 AOM-SOS score | Standard Deviation 2.38 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 9 | 1.41 AOM-SOS score | Standard Deviation 2.22 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 10 | 1.43 AOM-SOS score | Standard Deviation 2.36 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14 | Day 11 | 1.40 AOM-SOS score | Standard Deviation 2.27 |
Comparison: Null hypothesis: There is no difference between the two groups regarding the symptom burden as measured by the respective mean scores over time.p-value: 0.07Generalized estimating equations
Secondary
The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season
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.
Population: The analysis was ITT. The number of participants is equal to the number of children randomized \& eligible.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season | Study product | 14.72 days | Standard Deviation 6.77 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season | Other systemic antibiotic | 6.19 days | Standard Deviation 9.33 |
| Amoxicillin-Clavulanate, 10 Days | The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season | All systemic antibiotics | 20.91 days | Standard Deviation 12.7 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season | Study product | 6.79 days | Standard Deviation 3.01 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season | Other systemic antibiotic | 7.98 days | Standard Deviation 10.94 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season | All systemic antibiotics | 14.77 days | Standard Deviation 12.1 |
Comparison: 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.p-value: <0.001Regression, Linear
Secondary
The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within 60 Days of Enrollment
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.
Population: The analysis was ITT. The participants are randomized \& eligible children having follow-up beyond day 16.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within 60 Days of Enrollment | 0.15 recurrences/relapses per month | Standard Deviation 0.24 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within 60 Days of Enrollment | 0.12 recurrences/relapses per month | Standard Deviation 0.23 |
Comparison: Null hypothesis: There is no difference between the two groups in the rate of recurrences/relapses within 60 days of enrollment.p-value: 0.23Regression, Poisson
Secondary
The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within the Entire Respiratory Season
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.
Population: The analysis was ITT. The participants are randomized \& eligible children having follow-up beyond day 16.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amoxicillin-Clavulanate, 10 Days | The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within the Entire Respiratory Season | 0.14 recurrences/relapses per months followed | Standard Deviation 0.18 |
| Amoxicillin-Clavulanate, 5 Days | The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within the Entire Respiratory Season | 0.12 recurrences/relapses per months followed | Standard Deviation 0.19 |
Comparison: Null hypothesis: There is no difference between the two groups in the rate of recurrences/relapses within the entire respiratory season.p-value: 0.22Regression, Poisson