Efficacy of Antimicrobials in Young Children with AOM

描述（由申请人提供）：对急性中耳炎（AOM）儿童的“观察等待”方法在几个欧洲国家已成为10年来6个月大儿童的标准护理方法。然而，大多数支持观察等待的报告都是基于荟萃分析，其中包括具有大量严重方法局限性的试验。美国儿科学会（American Academy of Pediatrics）和美国家庭医生学会（American Academy of Family Physicians）联合制定的美国医学会（AOM）管理指南，支持对6-24个月大的非严重疾病且诊断不确定的儿童和16 -24个月大的非严重疾病且无论诊断是否确定的儿童采用这种“观察等待”方法。目前尚不清楚抗菌素治疗在多大程度上对急性中耳炎儿童有益，无论其疾病的严重程度如何。可能的情况是，“观察等待”方法可以安全地扩展到包括患有严重疾病和/或某些诊断的6-23个月大的儿童，或者另一方面，即使患有非严重疾病的儿童也会从抗菌药物治疗中充分受益，从而证明其使用是合理的。拟议的研究旨在克服早期研究的方法问题，并在受这种常见疾病影响最大的儿童群体（6-23个月）中解决这一重要的公共卫生问题。264名儿童将被纳入一项随机、安慰剂对照、双盲临床试验，由匹兹堡儿童医院（children Hospital of Pittsburgh）及其附属儿科诊所的耳镜专家进行。主要结果将在早期治疗访问（第4-5天）进行评估，并将比较阿莫西林-克拉维酸酯与安慰剂的临床疗效。治疗组间比较的次要结局包括：(1)治疗结束访问时的临床疗效（第10-12天），(2)治疗前7天和研究访问时的症状负担（采用3种全球量表），(3)在用药72小时前症状恶化的儿童比例，(4)儿童父母给药的镇痛药物数量，(5)不良事件，(6)对鼻咽细菌定群的影响，(7)鼓室测量结果，(8)直接和间接医疗费用，(9)父母对治疗的满意度。我们假设用阿莫西林-克拉维酸治疗的儿童的最低总体临床治愈率为85%。因此，每个治疗组总共有120名可评估的儿童，将允许检测到与安慰剂的15%差异（85%对70%），在显著性水平0.05（双尾）下，80%的功率。这项针对6-23个月儿童的精心设计的临床试验将解决一个在以前的研究中没有得到满意解决的特别关注的问题，即抗菌药物治疗与镇痛药物治疗是否比单独镇痛药物治疗更早、更全面地改善患有AOM的幼儿的整体临床状况（包括不适的缓解）。这种早期和更彻底的改善可能是抗菌治疗最重要的好处。

DESCRIPTION (provided by applicant): A "watchful waiting" approach for children with acute otitis media (AOM) has been the standard of care for 10 years in several European countries for children as young as 6 months of age. However, most reports endorsing watchful waiting are based on meta-analyses which include trials characterized by numerous and serious methodological limitations. AOM management guidelines jointly developed by the American Academy of Pediatrics and the American Academy of Family Physicians endorsed this "watchful waiting" approach in children 6-24 months with non-severe disease and uncertain diagnosis and in children >24 months with non-severe disease regardless of certainty of diagnosis. It remains unclear to what extent antimicrobial treatment is of benefit in young children with AOM, irrespective of the severity of their illness. It may be the case either that the "watchful waiting" approach might safely be extended to include children aged 6-23 months with severe illness and/or certain diagnosis, or on the other hand, that even children with nonsevere illness would benefit sufficiently from antimicrobial treatment to justify its use. The proposed study is designed to overcome the methodological problems of earlier studies and to address this important public health issue in the group of children (6-23 months of age) who experience the greatest impact of this common condition. 264 children will be enrolled in a randomized, placebo-controlled, double-blind clinical trial to be conducted by validated otoscopists at Children's Hospital of Pittsburgh and at an affiliated pediatric practice. Primary outcome will be assessed at the early on-therapy visit (Day 4-5) and will compare the clinical efficacy of amoxicillin-clavulanate vs. placebo. Secondary outcomes to be compared between treatment groups include: (1) clinical efficacy at the end-of-therapy visit (Day 10-12), (2) symptom burden (using 3 global scales) during each of the first 7 days of therapy and at study visits, (3) proportion of children who develop worsening symptoms before 72 hours of medication, (4) quantity of analgesic medication administered by children's parents, (5) adverse events, (6) effects on nasopharyngeal bacterial colonization, (7) tympanometric outcomes, (8) direct and indirect medical costs, and (9) parental satisfaction with therapy. We assume a minimum overall clinical cure rate of 85% for children treated with amoxicillin-clavulanate. Accordingly, a total of 120 evaluable children per treatment group will allow detection of a 15% difference from placebo (85% vs. 70%), with 80% power at a significance level of 0.05 (two-tailed). This carefully designed clinical trial in children 6-23 months will address an issue of particular concern that has not been satisfactorily addressed in previous studies, whether antimicrobial treatment along with analgesic treatment offers young children with AOM an earlier and more complete overall clinical improvement (including relief of discomfort) than analgesic treatment alone. This earlier and more complete improvement may constitute the most important benefit of antimicrobial treatment.