Official Title: “Efficacy of Antimicrobials in Young Children With Acute Otitis Media (AOM)”

The purpose of this study is to learn whether or not all children with ear infections (acute otitis media or AOM) should be treated with antibiotics. The study will compare two treatment strategies, "watchful waiting" or treatment with antibiotics, to determine which is more appropriate for children with AOM. About 268 children in Pittsburgh, between the ages of 6-23 months, with AOM will be enrolled in the study. They will be treated either with Augmentin (an antibiotic) or placebo for 10 days and closely followed for about 1 month. Parents will be asked to write information about their child in a Patient Diary. A general physical exam, including an ear exam, will be performed 4 times during the study. A mucus sample will be collected from the back of each child's nose. Parents will be asked questions during phone calls and at every visit. If a child has not improved or has worsened, the investigators will prescribe a different antibiotic that is known to kill resistant germs.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: March 2009

The purpose of this randomized, double-masked, placebo-controlled, single-center clinical trial is to determine the efficacy of antimicrobials in young children with acute otitis media (AOM). The primary objective is to compare time to resolution of symptoms in children receiving amoxicillin-clavulanate (90/6.4mg/kg/day in 2 divided doses for 10 days) to children receiving placebo (in 2 divided doses for 10 days). The secondary objectives are to:

evaluate the clinical efficacy of amoxicillin-clavulanate vs. placebo at the on-therapy visit (Day 4-5, and at least 72 hours after initial dose of study medication); evaluate the clinical efficacy of amoxicillin-clavulanate vs. placebo at the end-of-therapy (Day 10-12); compare symptom burden (as assessed by the AOM-Severity of Symptoms [AOM-SOS] and AOM-Faces scales) between treatment groups during each of the first 7 days of therapy and at all study visits; compare the proportion of children in each treatment group who develop worsening symptoms before having received 72 hours of study medication; compare the two treatment groups regarding the quantity of analgesic medication administered by children's parents; compare the incidence of adverse events accompanying the two treatment regimens; compare the effects of amoxicillin-clavulanate vs. placebo on the overall proportion of children with nasopharyngeal (NP) colonization with AOM pathogens (S. pneumoniae, H. influenzae, M.

catarrhalis, S. pyogenes), and on the proportion of children with NP colonization with penicillin non-susceptible S. pneumoniae; compare the 2 treatment groups regarding tympanometric outcomes at the on-therapy (Day 4-5), end-of-therapy (Day 10-12) and follow-up (Day 21-25) visits, using an algorithm that permits estimation of the probability of middle ear effusion given any particular tympanographic configuration; compare direct and indirect medical costs between the two treatment groups; and compare parental satisfaction with therapy between the two treatment groups. Participants will include 268 children, aged 6 to 23 months, diagnosed with acute otitis media in Western Pennsylvania. These participants will be recruited into the study at Children's Hospital of Pittsburgh (CHP), Pittsburgh, PA, and Armstrong Pediatrics (Children's Community Pediatrics: an affiliate of CHP) in Kittanning, PA. Subjects will be randomized to receive either Augmentin or placebo twice daily for 10 days. Parents of the subject will be asked to track symptom status, medication use (study medication and acetaminophen), fever and diarrhea in a study memory aid. Study procedures will include a medical history, vital signs, weight, clinical information regarding signs and symptoms of infection, nasopharyngeal specimens, and a physical exam including a tympanometry. Each child will be examined three additional times: 4-5 days after starting the medicine, study day 10-12 and 21-25 days after enrolling in the study. During these visits, study staff will review the child's symptoms and examine the child's ears. The study staff will also obtain a nasopharyngeal culture in order to look for resistant bacteria and to make appropriate changes in antibiotic treatment. Daily telephone assessments will be made by study staff on days 2, 3, and 4 of therapy to make sure the child is getting better. The study staff will see a child anytime a parent feels their child has not improved or has worsened. The primary outcome of the study is the time to resolution of symptoms where resolution is determined based on AOM-SOS scores.

Intervention(s) in this Clinical Trial

• Drug: Amoxicillin-clavulanate
  • Augmentin ES-600™: Amoxicillin-clavulanate potassium (600/42.9 mg per 5 mL), administered at a dose of 90/6.4 mg/kg/day in 2 divided doses for 10 days with strawberry cream flavor.
• Drug: Placebo
  • Same base formulation of the licensed product Augmentin ES-600™, with the same strawberry cream flavor.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A
  • Reconstituted amoxicillin-clavulanate at 90/6.4 mg/kg/day in 2 divided doses for 10 days.
• Placebo Comparator: B
  • Reconstituted placebo in 2 divided doses for 10 days.

Primary Measures

• Safety: occurrence of protocol defined diarrhea.
  • Time Frame: 3 or more watery stools in 1 day or 2 watery stools per day for 2 consecutive days
    Safety Issue?: Yes
• Compare time to resolution of symptoms in children receiving amoxicillin-clavulanate to children receiving placebo.
  • Time Frame: Duration of study
    Safety Issue?: No

Secondary Measures

• Evaluate clinical efficacy of amoxicillin-clavulanate vs. placebo at the on-therapy visit.
  • Time Frame: Day 4-5 and at least 72 hours after initial dose of study medication
    Safety Issue?: No
• Evaluate clinical efficacy of amoxicillin-clavulanate vs. placebo at the end of therapy.
  • Time Frame: Day 10-12
    Safety Issue?: No
• Compare the symptom burden between treatment groups.
  • Time Frame: During the first 7 days of therapy and all study visits
    Safety Issue?: No
• Compare the proportion of children in each treatment group who develop worsening symptoms.
  • Time Frame: Before receiving 72 hours of study medication
    Safety Issue?: No
• Compare the 2 treatment groups regarding the quantity of analgesic medication administered by children's parents.
  • Time Frame: First 7 days of therapy
    Safety Issue?: No
• Compare the incidence of adverse events accompanying the 2 treatment regimens.
  • Time Frame: Duration of study
    Safety Issue?: Yes
• Compare effects of amoxicillin-clavulanate vs. placebo on overall proportion of children with nasopharyngeal (NP) colonization with AOM pathogens and on the proportion of children with NP colonization with penicillin non-susceptible S. pneumoniae.
  • Time Frame: Day 10-12 and Day 21-25
    Safety Issue?: No
• Compare the 2 treatment groups regarding tympanometric outcomes using an algorithm that permits estimation of the probability of middle ear effusion given any particular tympanographic configuration.
  • Time Frame: Day 4-5, Day 10-12, and Day 21-25
    Safety Issue?: No
• Compare direct and indirect medical costs between the 2 treatment groups.
  • Time Frame: Follow-up assessment visits
    Safety Issue?: No
• Compare parental satisfaction with therapy between the 2 treatment groups.
  • Time Frame: Day 4-5, Day 10-12, and Day 21-25
    Safety Issue?: No

Inclusion Criteria:

• aged 6 to 23 months
• have received at least two doses of pneumococcal conjugate vaccine (Prevnar) and Haemophilus influenzae type B vaccine
• have evidence of acute otitis media (AOM) defined as: Recent (within 48 hours), onset of signs and symptoms and a score of greater than or equal to 3 on the AOM-SOS scale.

Middle ear effusion evidenced by at least two of the following:

• decreased or absent tympanic membrane mobility by pneumatic otoscopy,
• yellow or white discoloration of the tympanic membrane,
• opacification of the tympanic membrane, plus
• 1+ bulging of the tympanic membrane with either marked erythema or otalgia, or
• 2+ or 3+ bulging of the tympanic membrane

Exclusion Criteria:

• certain signs or symptoms (e.g., toxic appearance [capillary refill greater than 3 seconds, systolic blood pressure less than 60 mm Hg], otalgia for a period greater than 48 hours, spontaneous perforation of the tympanic membrane and drainage or temperature greater than or equal to 105 degrees F);
• clinical or anatomical characteristics that might obscure response to treatment (e.g., tympanostomy tube[s] in place or a history of tympanostomy tubes, unrepaired or repaired overt or submucous cleft palate, high-arched palate, or Down's syndrome);
• underlying systemic problems that might obscure response to infection (e.g., serious underlying disease [e.g., cystic fibrosis, neoplasm, juvenile diabetes]), concomitant infection that would preclude evaluation of the response of the child's AOM to study medication, known renal insufficiency (i.e., serum creatinine greater than or equal to 1.5 times upper limit of normal for age), known hepatic insufficiency or a history of amoxicillin-clavulanate-associated cholestatic jaundice or hepatic dysfunction, history of immune dysfunction, deficiency or receipt of immunosuppressive therapy, chronic gastrointestinal conditions (i.e., malabsorption, inflammatory bowel disease), malignancy;
• sensorineural hearing loss either unilateral or bilateral;
• comedications (e.g., systemic corticosteroids at any point while enrolled in the study, more than one dose of systemic antimicrobial therapy within 96, any investigational drug or vaccine;
• hypersensitivity to penicillin, amoxicillin or amoxicillin-clavulanate, or phenylketonuria or known hypersensitivity to aspartame;
• unable to complete the study protocol or not having access to a telephone; and
• current enrollment in another study or previously enrolled in this study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 6 Months

Maximum Age for this Clinical Trial: 23 Months

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Overall Clinical Trial Officials and Contacts

Overall Contact: Alejandro Hoberman (412) 692-5249 

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00377260

Study ID Number: 05-0142

ClinicalTrials.gov Identifier: NCT00377260

Health Authority: United States: Institutional Review Board