Clinical trial NCT01511107: Efficacy of Short-Course Antimicrobial Treatment for Children With Acute Otitis Media and Impact on Resistance
Official title: A Phase 2b, Multicenter, Randomized, Double Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy of Short-Course Antimicrobial Therapy for Young Children With Acute Otitis Media (AOM) and Impact on Antimicrobial Resistance
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Otitis Media
Keywords: acute otitis media
ear infection
antimicrobial therapy
antimicrobial resistance
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2012-01-18
Enrollment: 520
Sex: ALL
Minimum age (years): 6
Maximum age (years): 23
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: From 72 hours after randomization until day 21 of the index episode. The mean day for this visit was 13.2.
Secondary outcomes:
measure: The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit
timeFrame: From 72 hours after the AOM recurrence was diagnosed until day 21 of the recurrence. The mean day for this visit was 13.3.
measure: 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
timeFrame: The day 12-14 visit. The mean day for this visit was 13.3.
measure: 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
timeFrame: The day 12-14 visit. The mean day for this visit was 13.4.
measure: 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
timeFrame: The day 12-14 visit. The mean day for this visit was 13.2.
measure: 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
timeFrame: The day 12-14 visit. The mean day for this visit was 13.9.
measure: 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
timeFrame: The end-of-treatment visit. The mean day for this visit was 13.6.
measure: 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
timeFrame: The end-of-treatment visit. The mean day for this visit was 13.4.
measure: 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
timeFrame: Day 1 of study entry until day 365
measure: The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered
timeFrame: Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
measure: 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
timeFrame: The day 12-14 visit specific to the index episode. The mean day for this visit was 13.4.
measure: 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
timeFrame: The day 12-14 visit following a recurrence. The mean day for this visit was 13.6.
measure: 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
timeFrame: The day 12-14 visit specific to the index episode. The mean day for this visit was 13.4.
measure: 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
timeFrame: The day 12-14 visit following a recurrence. The mean day for this visit was 13.6.
measure: The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment
timeFrame: Day 1 of study entry until day 60.
measure: The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season
timeFrame: Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
measure: The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within 60 Days of Enrollment
timeFrame: Day 1 of study entry until day 60.
measure: The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within the Entire Respiratory Season
timeFrame: Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
measure: The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season
timeFrame: Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
measure: The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14
timeFrame: From day 6 of administration of study product until day 14 for all episodes
measure: The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product
timeFrame: Day 1 of administration of study product until day 16 for all episodes
measure: The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product
timeFrame: Day 1 of administration of study product until day 16 for all episodes
Other outcomes:
Locations:
city: Bardstown
country: United States
facility: Kentucky Pediatric/Adult Research
state: Kentucky
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Alejandro Hoberman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hoberman A, Paradise JL, Rockette HE, Kearney DH, Bhatnagar S, Shope TR, Martin JM, Kurs-Lasky M, Copelli SJ, Colborn DK, Block SL, Labella JJ, Lynch TG, Cohen NL, Haralam M, Pope MA, Nagg JP, Green MD, Shaikh N. Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children. N Engl J Med. 2016 Dec 22;375(25):2446-2456. doi: 10.1056/NEJMoa1606043.
citation: Martin JM, Hoberman A, Paradise JL, Barbadora KA, Shaikh N, Bhatnagar S, Shope T, Block SL, Haralam MA, Kurs-Lasky M, Colborn DK, Green M. Emergence of Streptococcus pneumoniae serogroups 15 and 35 in nasopharyngeal cultures from young children with acute otitis media. Pediatr Infect Dis J. 2014 Nov;33(11):e286-90. doi: 10.1097/INF.0000000000000445.