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

Phase 2

Terminated

• Conditions: Acute Otitis Media
• Interventions: Drug: Amoxicillin-Clavulanate, 10 days; Drug: Amoxicillin-Clavulanate, 5 days

• Registration Number: NCT01511107
• Lead Sponsor: Alejandro Hoberman

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.

Study Timeline

• Study Start: 2012-01
• Study First Submitted: 2012-01-10
• Study First Submitted QC: 2012-01-13
• Study First Posted: 2012-01-18
• Primary Completion: 2015-09
• Study Completion: 2015-10
• Results First Submitted: 2016-09-30
• Results First Submitted QC: 2016-12-19
• Results First Posted: 2017-02-10
• Status Verified: 2017-10
• Last Update Submitted: 2017-10-05
• Last Update Posted: 2017-10-06

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 520

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Amoxicillin-Clavulanate, 10 days	Amoxicillin-Clavulanate, 10 days	amoxicillin-clavulanate, 90/6.4 mg/kg/day, 2 divided doses, 10 days
Amoxicillin-Clavulanate, 5 days	Amoxicillin-Clavulanate, 5 days	amoxicillin-clavulanate, 90/6.4 mg/kg/day, 2 divided doses, 5 days plus placebo, 2 divided doses, 5 days

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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 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 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 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 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 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 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 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.
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.

Trial Locations

Locations (2)

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

Kentucky Pediatric/Adult Research; 🇺🇸 Bardstown, Kentucky, United States