Efficacy of Tympanostomy Tubes for Children With Recurrent Acute Otitis Media

Study Overview
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Brief Summary
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To determine whether tympanostomy tube placement (TTP) compared with nonsurgical management will meaningfully improve children's acute otitis media (AOM) experience over the succeeding 2 years.

Detailed Description
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Tympanostomy tube placement (TTP) for recurrent acute otitis media (rAOM) is frequently performed in children under 3 years of age; however, a critical need exists to establish its risk/benefit ratio. Seventy percent of children experience at least one episode of AOM during the first year of life; 20% of children have rAOM. The efficacy of TTP for preventing rAOM, assumedly by maintaining middle-ear ventilation, remains unclear. Benefits of TTP must be balanced against risks of anesthesia, complications and sequelae of surgery, and cost. Accordingly, the objective of this proposal is to determine the efficacy of TTP in children aged 6-35 months, the group in which rAOM is most troublesome. The central hypothesis is that in children with rAOM, the operation will prove effective over the ensuing 2 years overall, but the benefit in a more severely affected, and therefore higher-risk subgroup may be substantially greater than in a less severely affected subgroup, in whom benefits may not outweigh risks. The rationale for this research is based on a belief that the limited nature of the benefit of TTP found in earlier clinical trials may have been the result of enrolling children whose illnesses had not been diagnosed using stringent criteria and/or whose ascertainment of episodes had relied on undocumented histories. The primary objective is to determine the extent to which TTP reduces the overall rate of recurrences in children with rAOM over a 2-year period. In a randomized, clinical trial, children aged 6-35 months who are at risk for rAOM will be followed prospectively and examined promptly with new respiratory illnesses to accurately document episodes of AOM. A total of 240 children who meet stringent inclusion criteria for rAOM will be eligible to undergo randomization within strata (age and exposure to other children) to receive TTP or nonsurgical management. Children will be followed for 2 years; the average number of episodes of AOM will be documented and compared between groups. The secondary objective is to determine changes following TTP in nasopharyngeal (NP) colonization with resistant bacteria. At the time of randomization and 3 times a year for 2 years, NP specimens will be obtained and cultured. Susceptibility testing and serotyping will be performed, and the proportions of children colonized with resistant bacteria compared between treatment groups. The tertiary objective is to determine cost-effectiveness of TTP. The investigators will calculate both direct medical and nonmedical costs and correlate this with the number of days that each child has AOM symptoms, otorrhea, and any adverse events or complications. The proposed research is innovative, as the investigators will document AOM episodes prospectively using stringent diagnostic criteria and obtain digital tympanic membrane images otoendoscopically to enhance accuracy of observations. Findings of the proposed study will provide clinicians and parents with dependable evidence concerning the overall effects of TTP compared with nonsurgical management in children with rAOM of varying degrees of severity, enabling evidence-based decisions regarding an important component of the children's healthcare.

Official Title
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Efficacy of Tympanostomy Tubes for Children With Recurrent Acute Otitis Media

Conditions
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Acute Otitis Media

Intervention / Treatment
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* Device: Tympanostomy tube placement
* Drug: Amoxicillin-Clavulanate and/or Ceftriaxone
* Drug: Ofloxacin Otic


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria are aged 6-35 months, have rAOM, defined as the occurrence of 3 AOM episodes in 6 months or 4 episodes in 12 months with ≥1 episode in the preceding 6 months, and 2 of these AOM episodes have been documented by trained study personnel. Exclusion Criteria have a history of TTP, have a chronic illness (cystic fibrosis, neoplasm, juvenile diabetes, renal or hepatic insufficiency, immune dysfunction, malabsorption, inflammatory bowel disease, severe asthma requiring at least 4 courses of oral corticosteroids during the last 12 months), are allergic to amoxicillin, have a congenital anomaly that might increase the risk of recurrences (e.g., cleft palate, Down's syndrome), have had otitis media effusion for at least 3 months in addition to rAOM, or have sensorineural hearing loss.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 35 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Surgical Management<br>Tympanostomy Tube Placement Topical antimicrobial treatment of acute otitis media episodes with ofloxacin drops | Device: Tympanostomy tube placement<br>* As per routine care, tympanostomy tubes will be inserted under general anesthesia, using a small radial incision in the anteroinferior portion of the tympanic membrane; a Teflon® Armstrong-type tympanostomy tube will be used.<br>Drug: Ofloxacin Otic<br>* Participants randomized to receive tympanostomy tubes will also be followed overtime for recurrences of AOM and treated with topical ofloxacin (Floxin® 0.3%, 5 mL) 5 drops into the affected ear twice daily for 10 days. Persistence of otorrhea after 7 days of treatment will be considered inadequate response, and children so affected will be prescribed empiric amoxicillin-clavulanate (90/6.4 mg/kg/day in two divided doses) followed by culture-directed therapy 48 hours later.<br>|
| Other: Non-Surgical Management<br>Antimicrobial treatment of acute otitis media episodes with amoxicillin-clavulanate and/or ceftriaxone | Drug: Amoxicillin-Clavulanate and/or Ceftriaxone<br>* Children randomized to nonsurgical management will receive stepwise therapy with amoxicillin-clavulanate (90/6.4 mg/kg in two divided doses for 10 days), and in the event of inadequate response, ceftriaxone (75 mg/kg intramuscularly, repeated in 48 hours), as recommended in the American Academy of Pediatrics guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Rate of Occurrence of Acute Otitis Media (AOM) Episodes Per Child-Year | An episode of AOM is considered a discrete occurrence if symptoms and signs persisted for, or recurred, 17 or more days after the start of antimicrobial treatment. The rate is calculated by dividing the total number of occurrences by the total number of years of follow-up. Multiple imputation was used when follow-up was incomplete. | Day 1 until Day 786. The mean length of actual follow-up was 662 days / 1.8 years. For each child with incomplete 2-year follow-up, multiple imputation was used and values for the remaining days/years were imputed. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Rate of Occurrence of Acute Otitis Media (AOM) Episodes Per Child-Year According to the Estimated Risk of Acute Otitis Media (AOM) Recurrences at Enrollment | An episode of AOM is considered a discrete occurrence if symptoms and signs persisted for, or recurred, >=17 days after the start of antimicrobial treatment. The rate is calculated by dividing the total # of occurrences by the total # of years of follow-up. Risk of recurrences was based on early age of onset of AOM; numerous and/or frequent previous AOM episodes; receipt of multiple courses of antibiotic; eligibility for enrollment first evident during warm-weather months; parental characterization of previous AOM episodes as severe; eligibility for enrollment despite nonexposure to other young children; moderate or marked tympanic membrane (TM) bulging with previous AOM episodes; most previous AOM episodes in both ears; and a high score on the Acute Otitis Media Severity of Symptom scale (with scores ranging from 0 to 10 and higher scores indicating greater severity of symptoms) during screening and/or at enrollment. Multiple imputation was used when follow-up was incomplete. | Day 1 until Day 786. The mean length of actual follow-up was 662 days / 1.8 years. For each child with incomplete 2-year follow-up, multiple imputation was used and values for the remaining days/years were imputed. | 
| The Frequency Distribution of AOM Episodes Among Children Completing the Study | An episode of AOM is considered a discrete occurrence if symptoms and signs persisted for, or recurred, 17 or more days after the start of antimicrobial treatment. Children with at least 23 months of follow-up were considered to have completed the study. | Day 1 until Day 786. For children completing the study, the mean length of follow-up was 726 days. | 
| The Distribution of Children Experiencing Treatment Failure (TF) | Parents used the Acute Otitis Media Severity of Symptoms (AOM-SOS) scale (version 4.0) to rate each of 5 symptoms as none, a little, or a lot, with corresponding scores of 0, 1, and 2. Total scores range from 0 to 10; higher scores indicate greater severity of symptoms. AOM episodes were categorized as likely severe if the parent described the child as having moderate or severe otalgia (a lot of ear tugging), temperature ≥39°C, or an AOM-SOS scale score >6 Day 1 of the episode. TF is defined as frequent AOM recurrences (2 in 3 months, 3 in 6 or 4 in 12); ≥3 likely severe AOM recurrences, receipt of ≥45 cumulative days of systemic antimicrobial treatment for AOM, otorrhea for ≥45 cumulative days or diarrhea associated with antimicrobial treatment for ≥30 cumulative days, respectively, in 12 months; persistent effusion for ≥12 successive months; TM perforation for ≥90 days; AOM related hospitalization; anesthesia reactions; and tubes in children randomized to nonsurgical management. | Day 1 until Day 786. | 
| The Time to the First Episode of AOM | The time to the first episode of AOM is defined as the time, expressed in months, from randomization until the first episode of AOM. | Day 1 until Day 786. The mean length of follow-up was 662 days / 21.8 months. | 
| The Distribution of AOM Episodes Categorized as Probably Severe or Probably Nonsevere | The American Academy of Pediatrics clinical practice guideline concerning the management of AOM refers to children with severe signs or symptoms as those with moderate or severe otalgia or otalgia for >= 48 hours or temperature 39°C (102.2°F) or higher. To simulate that definition, scores are used from the 5-item Acute Otitis Media Severity of Symptoms (AOM-SOS) scale (version 4.0) in which parents are asked to rate symptoms, as compared with the child's usual state, as none, a little, or a lot, with corresponding scores of 0, 1, and 2. Total scores range from 0 to 10, with higher scores indicating greater severity of symptoms. AOM episodes are categorized as probably severe if the parent described the child as having had moderate or severe otalgia (a lot of ear tugging; i.e. a score of 2), temperature >=39°C, or an AOM-SOS scale score >6 on Day 1 of the episode. If not probably severe, then the episode is categorized as probably nonsevere. | Day 1 until Day 786. | 
| The Distribution of AOM Episodes Presenting With Tympanic Membrane Bulging or Otorrhea | The presence of either tympanic membrane bulging or tympanic membrane perforation with purulent otorrhea, in addition to documentation of symptoms, is required for each episode of AOM. | Day 1 until Day 786. | 
| The Mean Days Per Year Children Experience Tube Otorrhea | Adverse events, including tube-associated otorrhea, were collected from enrollment through the end of study. Each study visit included a review of adverse events. Any such event that occurred since the previous visit was recorded, including the date of onset and the date of resolution. For each child, the days per year of tube otorrhea is calculated by dividing the total number of days of tube otorrhea (based on dates of onset and resolution) by the total number of years of follow-up. | Day 1 until Day 786. The mean length of follow-up was 662 days / 1.8 years. | 
| The Mean Days Per Year Children Experience AOM Symptoms With an Intact Tympanic Membrane (TM) | For a given child, if a day of follow-up coincides with a study visit, the status of the right and left TMs are recorded at the ear exam. If a day of follow-up does not coincide with a study visit the status of each TM is assumed to be the same as the status on the prior day. Scores are used from the 5-item Acute Otitis Media Severity of Symptoms (AOM-SOS) scale (version 4.0) in which parents are asked to rate symptoms, as compared with the child's usual state, as none, a little, or a lot, with corresponding scores of 0, 1, and 2. Total scores range from 0 to 10, with higher scores indicating greater severity of symptoms. Scores are recorded at study visits and on diaries. The total number of days with an intact TM and a AOM-SOS score greater than or equal to 1 is divided by the total number of years of follow-up to arrive at the days per year with AOM symptoms and an intact TM. | Day 1 until Day 786. The mean length of follow-up was 662 days / 1.8 years. | 
| The Mean Days Per Year Children Receive Systemic Antimicrobials for AOM | Systemic antibiotics include Amoxicillin-Clavulanate, Ceftriaxone, Cefdinir, Amoxicillin, Azithromycin, Clindamycin, Levofloxacin, Bactrim, Cefprozil, Omnicef and Trimethoprim-Sulfamethoxazole. The days per year, for each child, is calculated by dividing the total number of days the child receives systemic antimicrobials for AOM (based on the recorded start and stop dates) by the total number of years of follow-up. | Day 1 until Day 786. The mean length of follow-up was 662 days / 1.8 years. | 
| The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported | PDD is defined as the occurrence of three or more watery stools on 1 day or two or more watery stools on each of 2 consecutive days. Adverse events, including PDD, were collected from enrollment through the end of study. Each study visit included a review of medication-related adverse events. Any such event that occurred since the previous visit was recorded. | Day 1 until Day 786. | 
| The Distribution of Children for Whom Diaper Dermatitis Was Reported | Diaper dermatitis is defined as diaper rash necessitating administration of topical antifungal therapy. Adverse events, including diaper dermatitis, were collected from enrollment through the end of study. Each study visit included a review of medication-related adverse events. Any such event that occurred since the previous visit was recorded. | Day 1 until Day 786. | 
| The Distribution of Children for Whom Tube Otorrhea Was Reported | Adverse events, including tube-associated otorrhea, were collected from enrollment through the end of study. Each study visit included a review of adverse events. Any such event that occurred since the previous visit was recorded. | Day 1 until Day 786. | 
| The Distribution of Children With a Penicillin-Nonsusceptible Nasopharyngeal or Throat Isolate At Any Follow-up Visit According to the Colonization Status at Enrollment | Throat specimens were obtained mainly from children older than 24 months of age. The penicillin-nonsusceptible pathogens considered are penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae and ß-lactamase-positive Haemophilus influenzae. Susceptibility to penicillin was defined as follows: susceptible as a minimum inhibitory concentration (MIC) of <0.1 μg/mL; intermediate as an MIC of 0.1 to 1μg/mL; and resistant as an MIC of >1 μg/mL. | Day 1 until Day 786. | 
| The Distribution of Nonsusceptible Nasopharyngeal or Throat Pathogens Recovered at Episodes of AOM | Throat specimens were obtained mainly from children older than 24 months of age. The penicillin-nonsusceptible pathogens considered are penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae (S. pn) and ß-lactamase-positive Haemophilus influenzae (H. flu). Susceptibility to penicillin was defined as follows: susceptible as a minimum inhibitory concentration (MIC) of <0.1 μg/mL; intermediate as an MIC of 0.1 to 1μg/mL; and resistant as an MIC of >1 μg/mL. | Day 1 until Day 786. | 
| The Distribution of Nonsusceptible Nasopharyngeal or Throat Pathogens Recovered at Routine Non-Illness Visits | Throat specimens were obtained mainly from children older than 24 months of age. The penicillin-nonsusceptible pathogens considered are penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae (S. pm) and ß-lactamase-positive Haemophilus influenzae (H. flu). Susceptibility to penicillin was defined as follows: susceptible as a minimum inhibitory concentration (MIC) of <0.1 μg/mL; intermediate as an MIC of 0.1 to 1μg/mL; and resistant as an MIC of >1 μg/mL. | Day 1 until Day 786. | 
| The Distribution of Nonsusceptible Nasopharyngeal or Throat Pathogens Recovered at AOM Episodes Late During the Respiratory Season (April-May) | Throat specimens were obtained mainly from children older than 24 months of age. The penicillin-nonsusceptible pathogens considered are penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae (S. pn) and ß-lactamase-positive Haemophilus influenzae (H. flu). Susceptibility to penicillin was defined as follows: susceptible as a minimum inhibitory concentration (MIC) of <0.1 μg/mL; intermediate as an MIC of 0.1 to 1μg/mL; and resistant as an MIC of >1 μg/mL. | April 1 to May 31, each of the 2 years of follow-up. The mean length of follow-up was 111 days / 3.7 months. | 
| The Mean Score Representing Parental Satisfaction With Clinical Management | At the end-of-study visit, parents were asked to rate their level of satisfaction with their child's assigned management using a 5-point scale with higher numbers indicating greater satisfaction, specifically 1 = very dissatisfied, 2 = somewhat dissatisfied, 3 = neither satisfied nor dissatisfied, 4 = somewhat satisfied, and 5 = very satisfied. | The end-of-study visit. The mean day for this visit was 726. | 
| The Distribution of Parent Reports Indicating At Least One Health Care Encounter Since the Previous Study Visit as an Indicator of Medical Resource Use | Health care encounters, indicators of medical resource use, were ascertained from parent reports. At scheduled study visits, every 8 weeks after randomization. and at interim sick study visits, parents were asked about encounters with healthcare providers, including hospitalizations and visits to emergency departments, urgent care, and primary care providers, since the previous study visit. | Day 1 until Day 786. | 
| The Distribution of Reported Occurrences of a Parent Missing Work Due to Child's Illness, as an Indicator of Non-Medical Resource Use | Occurrences of parent missing work due to child's illness, an indicator of non-medical resource use, was ascertained from parent reports at scheduled study visits, every 8 weeks after randomization, and at interim sick study visits. | Day 1 until Day 786. | 
| The Distribution of Reported Occurrences of the Need for Special Childcare Arrangements Due to Child's Illness, as an Indicator of Non-Medical Resource Use | Occurrences of the need for special childcare arrangements due to child's illness, an indicator of non-medical resource use, was ascertained from parent reports at scheduled study visits, every 8 weeks after randomization, and at interim sick study visits. | Day 1 until Day 786. | 
| The Mean Scores on the 6 Item Quality of Life Survey Questionnaire (OM-6) | The OM-6 is a 6 item quality of life assessment addressing physical suffering, hearing loss, speech impairment, emotional distress, activity limitations and caregiver concerns. Responses are regarded on an ordinal scale ranging from 1 (no problem) to 7 (greatest problem). The average response, i.e., score, for these 6 items is calculated. The overall child's quality of life (QOL) score, also captured on the OM-6, is expressed on an ordinal response scale that ranges from 0 (worst quality of life) to 10 (best quality). A OM-6 is administered to the parent every 16 weeks after randomization and occasionally at sick visits. | Day 1 until Day 786. | 
| The Mean Scores on the 6 Item Caregiver Impact Questionnaire (CIQ) | The Caregiver Impact Questionnaire (CIQ) is a 6 item assessment addressing lack of sleep, absence from work or education, canceling of family activities, changing daily activities, feeling nervous and feeling helpless. Each of these responses is expanded to a continuous scale from 0 (no impact on caregiver) to 100 (greatest impact). The average response, i.e., score, for these 6 items is calculated. The overall caregiver's quality of life (QOL) score, also captured on the CIQ, is expressed on a ordinal response scale that ranges from 0 (worst quality of life) to 10 (best quality). The CIQ is administered to the parent every 16 weeks after randomization and occasionally at sick visits. | Day 1 until Day 786. | 
| The Total Cost of Management of Recurrent Acute Otitis Media Per Quality Adjusted Life Days (QALDs) as a Measure of Cost-Effectiveness | Total costs in US dollars were calculated by summing costs of lost wages, office visits, medical procedures, hospitalizations, and medications. Total QALDs were calculated by summing daily utility values. A utility value of 1.0 was assumed for days without AOM, otorrhea, or hospitalization. For days where these states were reported, published utility values associated with each state were used. To arrive at the final measure, total costs were divided by total utility values. | Day 1 until Day 786. The mean length of actual follow-up was 662 days / 1.8 years. | 
| The Total Cost of Management of Recurrent Acute Otitis Media Per Quality Adjusted Life Days (QALDs) as a Measure of Cost-Effectiveness According to the Estimated Risk of Acute Otitis Media Recurrences at Enrollment | Total costs in US dollars were calculated by summing costs of lost wages, office visits, medical procedures, hospitalizations, and medications. Total QALDs were calculated by summing daily utility values. A utility value of 1.0 was assumed for days without AOM, otorrhea, or hospitalization. For days where these states were reported, published utility values associated with each state were used. To arrive at the final measure, total costs were divided by total utility values. The estimated risk of AOM at enrollment is described under both Baseline Characteristics and Outcome Measure #2. | Day 1 until Day 786. The mean length of actual follow-up was 662 days / 1.8 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ear infection, antibiotics, infants, children, pediatrics, tympanostomy tubes