Acute Otitis Media (AOM) Therapy Trial in Young Children

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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 objectives are to compare time to resolution of symptoms (initial and sustained) 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), and to compare the weighted average AOM-Severity of Symptoms (AOM-SOS) scores in the two groups during days 1-7. 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 visit (Day 10-12); compare 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 amoxicillin-clavulanate 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 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.

Official Title
-----------------
Efficacy of Antimicrobials in Young Children With Acute Otitis Media (AOM)

Conditions
-----------------
Acute Otitis Media

Intervention / Treatment
-----------------
* Drug: amoxicillin-clavulanate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 23 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amoxicillin-clavulanate<br>Reconstituted amoxicillin-clavulanate at 90/6.4 mg/kg/day in 2 divided doses for 10 days. | Drug: amoxicillin-clavulanate<br>* 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.<br>* Other names: amox-clav;|
| Placebo Comparator: Placebo<br>Reconstituted placebo in 2 divided doses for 10 days. | Drug: Placebo<br>* Same base formulation of the licensed product Augmentin ES-600™, with the same strawberry cream flavor.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time to Resolution of Symptoms, Defined as Acute Otitis Media-Severity of Symptoms (AOM-SOS) Score of 0 or 1, According to Treatment Assignment | Time to resolution of symptoms is defined as the time from randomization until a child's AOM-SOS score reaches 0 or 1. The parent rated each of 7 symptoms (ear tugging, crying, irritability, difficulty sleeping, diminished activity, diminished appetite & fever) as 0, 1 or 2 (none, a little, a lot) and recorded the ratings in a diary following enrollment on Day 1, twice daily Days 2 and 3, then once daily Days 4-7. Each set of ratings was summed to obtain an AOM-SOS score. The maximum possible score was 14 and the minimum was 0. A score >=3 was required to be enrolled in the study. | The first 7 days on therapy | 
| The Time to Resolution of Symptoms, Defined as Acute Otitis Media-Severity of Symptoms (AOM-SOS) Score of 0 or 1 on Two Consecutive Occasions, According to Treatment Assignment | Time to resolution of symptoms is defined as the time from randomization until a child's AOM-SOS score reaches <= 1 on two consecutive occasions. The parent rated each of 7 symptoms (ear tugging, crying, irritability, difficulty sleeping, diminished activity, diminished appetite & fever) as 0, 1 or 2 (none, a little, a lot) & recorded the ratings in a diary following enrollment on Day 1, twice daily Days 2 & 3, & once daily Days 4-7. Each set of ratings was summed to obtain an AOM-SOS score. The maximum possible was 14 and the minimum 0. A score >=3 was required to be enrolled in the study. | The first 7 days on therapy | 
| The Weighted Average Acute Otitis Media - Severity of Symptom (AOM-SOS) Score, According to Treatment Assignment | The AOM-SOS score is derived from parent scoring each of 7 symptoms (ear tugging, crying, irritability, difficulty sleeping, diminished activity, diminished appetite & fever) associated with AOM as 0, 1 or 2 (none, a little, a lot). The AOM-SOS was administered twice daily the first 3 days of follow-up, then daily for 4 additional days. Symptom burden for each child is determined by calculating the weighted average of symptom scores post-enrollment over the first 7 days of therapy. Scores are weighted by 1/k, where k is the number of post-enrollment assessments taken on that day. | During the first 7 days of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Distribution of Clinical Failures by the On-therapy Visit According to Treatment Assignment | Clinical failure by the on-therapy visit is defined as either failure to achieve substantial improvement in symptoms, or worsening of otoscopic signs, or both. | On-therapy visit. The mean day for this visit was 5.0. | 
| The Distribution of Clinical Failures by the End-of-therapy Visit According to Treatment Assignment | Clinical failure by the end of therapy visit is defined as failure to achieve complete or virtually complete resolution of symptoms and of otoscopic signs, but without regard to the persistence of middle ear effusion. | End-of-therapy visit. The mean day for this visit was 11.6. | 
| The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Score, Post-enrollment, Over the First 7 Days of Therapy According to Treatment Assignment | The parent rated each of 7 symptoms (ear tugging, crying, irritability, difficulty sleeping, diminished activity, diminished appetite & fever) as 0, 1 or 2 (none, a little, a lot) and recorded the ratings in a diary following enrollment on Day 1, twice daily Days 2 and 3, then once daily Days 4-7. Each set of ratings was summed to obtain an AOM-SOS score as a measure of symptom burden. The maximum possible score was 14 and the minimum was 0. | During the first 7 days of therapy | 
| The Distribution of Children Developing Worsening Symptoms Prior to Receiving 72 Hours of Study Medication According to Treatment Assignment | The parent rated each of 7 symptoms (ear tugging, crying, irritability, difficulty sleeping, diminished activity, diminished appetite & fever) as 0, 1 or 2 (none, a little, a lot) and recorded the ratings in a diary following enrollment on Day 1 and twice daily Days 2 and 3. Each set of ratings was summed to obtain an Acute Otitis Media-Severity of Symptoms (AOM-SOS) score. We compared a child's AOM-SOS scores in the first 72 hours to his/her score at enrollment to determine if a child's symptoms got worse (score increased) or remained unchanged or improved (score remained same or decreased). | Before receiving 72 hours of study medication | 
| The Mean Number of Times Analgesic Medication Was Administered to the Child According to Treatment Assignment | The parents were asked to complete a memory aid for the first 10 days of the study. One item asked them to record medications administered to the child in addition to the study medication. The data presented shows the mean number of times analgesic, i.e. ibuprofen or acetaminophen, was administered. | The first 10 days of follow-up | 
| The Distribution of Children With Observed or Parent Reported Adverse Events or Complications According to Treatment Assignment | Analysis was limited to those adverse events identified as being associated with either the study medication or the antimicrobials administered to children who were treatment failures or as being a complication of acute otitis media. | We monitored children and queried parents regarding adverse events at each study visit, i.e. Day 4-5, Day 10-12, and Day 21-25, and at interim visits. The last assessment was made at the Day 21-25 visit. The mean day for this visit was 22.8. | 
| The Distribution of Children With Nasopharyngeal (NP) Colonization With AOM Pathogens at the End-of-therapy Visit According to Treatment Assignment | AOM pathogens are defined as Streptococcus Pneumoniae or Haemophilus Influenzae or Moraxella Catarrhalis or Streptococcus Pyogenes. Nasopharyngeal cultures were obtained at the end of therapy visit. | End-of-therapy visit. The mean day for this visit was 11.6. | 
| The Distribution of Children With Nasopharyngeal (NP) Colonization With Penicillin-susceptible Streptococcus Pneumoniae (S. pn) at the End-of-therapy Visit According to Treatment Assignment |  | End-of-therapy visit. The mean day for this visit was 11.6. | 
| The Distribution of Children With Nasopharyngeal (NP) Colonization With AOM Pathogens at the Follow-up Visit According to Treatment Assignment | AOM pathogens are defined as Streptococcus Pneumoniae or Haemophilus Influenzae or Moraxella Catarrhalis or Streptococcus Pyogenes. Nasopharyngeal cultures were obtained at the follow-up visit. | Follow-up visit. The mean day for this visit was 22.8. | 
| The Distribution of Children With Nasopharyngeal (NP) Colonization With Penicillin-susceptible Streptococcus Pneumoniae (S. pn) at the Follow-up Visit |  | Follow-up visit. The mean day for this visit was 22.8. | 
| The Probability of Middle Ear Effusion, Based on an Algorithm That Estimates the Probability of Middle Ear Effusion From an Interpretable Tympanographic Configuration, at the On-therapy Visit According to Treatment Assignment | For tympanograms with values for height, middle-ear air pressure, and gradient width, the probability of Middle Ear Effusion (MEE) was estimated by applying an algorithm developed by Smith et al. If the tympanogram was flat and had no printed values for the 3 fields, the probability of MEE was estimated to be .802 based on the proportion of ears with flat graphs that were found otoscopically, by Smith et al, to have MEE. | On-therapy visit. The mean day for this visit was 5.0. | 
| The Probability of Middle Ear Effusion, Based on an Algorithm That Estimates the Probability of Middle Ear Effusion From an Interpretable Tympanographic Configuration, at the End-of-therapy Visit According to Treatment Assignment | For tympanograms with values for height, middle-ear air pressure, and gradient width, the probability of Middle Ear Effusion (MEE) was estimated by applying an algorithm developed by Smith et al. If the tympanogram was flat and had no printed values for the 3 fields, the probability of MEE was estimated to be .802 based on the proportion of ears with flat graphs that were found otoscopically, by Smith et al, to have MEE. | End-of-therapy visit. The mean day for this visit was 11.6. | 
| The Probability of Middle Ear Effusion, Based on an Algorithm That Estimates the Probability of Middle Ear Effusion From an Interpretable Tympanographic Configuration, at the Follow-up Visit According to Treatment Assignment | For tympanograms with values for height, middle-ear air pressure, and gradient width, the probability of Middle Ear Effusion (MEE) was estimated by applying an algorithm developed by Smith et al. If the tympanogram was flat and had no printed values for the 3 fields, the probability of MEE was estimated to be .802 based on the proportion of ears with flat graphs that were found otoscopically, by Smith et al, to have MEE. | Follow-up visit. The mean day for this visit was 22.8. | 
| The Mean Number of Visits to a Primary Care Provider (PCP) According to Treatment Assignment | At each visit parents were asked if they had taken their child to his/her primary care physician since the last contact. Medical records were also reviewed. | This was assessed at each study visit, i.e. Day 4-5, Day 10-12, Day 21-25, and at interim visits. The last assessment was made at the Day 21-25 visit. The mean day for this latter visit was 22.8. | 
| The Mean Number of Emergency Room Visits According to Treatment Assignment | At each visit we asked parents if they had to take their child to the emergency department. We also reviewed medical records to assure even more accurate reporting. | This was assessed at each study visit, i.e. Day 4-5, Day 10-12, Day 21-25, and at interim visits. The last assessment was made at the Day 21-25 visit. The mean day for this latter visit was 22.8. | 
| The Mean Number of Antibiotic Prescriptions, Exclusive of Study Medication, According to Treatment Assignment | This is the number of times, in the course of the study, a child required treatment with an antibiotic other than the blinded study medication. | This was assessed at each study visit, i.e. Day 4-5, Day 10-12, Day 21-25, and at interim visits. The last assessment was made at the Day 21-25 visit. The mean day for this latter visit was 22.8. | 
| The Total Number of Visits, Summed Across All Participants, at Which a Family Member Reported Having Missed Work According to Treatment Assignment | At each visit, parent or parents were asked if their child's illness had caused either parent to miss a day or partial day of work. The total number of visits is summed across all participants in the respective treatment arms. | This was assessed at each study visit, i.e. Day 4-5, Day 10-12, Day 21-25, and at interim visits. The last assessment was made at the Day 21-25 visit. The mean day for this latter visit was 22.8. | 
| The Total Number of Visits, Summed Across All Participants, at Which a Family Member Reported Making Special Daycare Arrangements According to Treatment Assignment | At each visit, parent or parents were asked if their child's illness had caused them to make alternative daycare arrangements. The total number of visits is summed across all participants in the respective treatment arms. | This was assessed at each study visit, i.e. Day 4-5, Day 10-12, Day 21-25, and at interim visits. The last assessment was made at the Day 21-25 visit. The mean day for this latter visit was 22.8. | 
| The Mean Score Representing Parental Satisfaction With the Study Medication As Recorded at the On-therapy Visit According to Treatment Assignment | Parents were asked to circle the expression that best represented their satisfaction with the study medication. These expressions have an assigned value: Very dissatisfied = 1, Somewhat dissatisfied = 2, Neither satisfied nor dissatisfied = 3, Somewhat satisfied = 4 and Very satisfied = 5. | On-therapy visit. The mean day for this visit was 5.0. | 
| The Mean Score Representing Parental Satisfaction With the Study Medication As Recorded at the End-of-therapy Visit According to Treatment Assignment | Parents were asked to circle the expression that best represented their satisfaction with the study medication. These expressions have an assigned value: Very dissatisfied = 1, Somewhat dissatisfied = 2, Neither satisfied nor dissatisfied = 3, Somewhat satisfied = 4 and Very satisfied = 5. | End-of-therapy visit. The mean day for this visit was 11.6. | 
| The Mean Score Representing Parental Satisfaction With the Study Medication As Recorded at the Follow-up Visit According to Treatment Assignment | Parents were asked to circle the expression that best represented their satisfaction with the study medication. These expressions have an assigned value: Very dissatisfied = 1, Somewhat dissatisfied = 2, Neither satisfied nor dissatisfied = 3, Somewhat satisfied = 4 and Very satisfied = 5. | Follow-up visit. The mean day for this visit was 22.8. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
acute otitis media, infants, children