Early Antipseudomonal Therapy in Cystic Fibrosis

描述(由申请人提供)： 本研究的目的是确定一种安全、有效和系统的方法来治疗儿童囊性纤维化(CF)中首次分离的铜绿假单胞菌(PA)。 人们对研究幼儿的抗假单胞菌疗法非常感兴趣，长期目标是延迟或预防导致不可逆转的肺部疾病的慢性感染。对侵袭性早期干预(即，在没有症状的情况下，仅首先隔离PA的干预)的长期临床和微生物学疗效或安全性的评估很少。虽然首次分离PA的抗假单胞菌治疗可能会在短期内从呼吸道培养中根除PA，但目前尚不清楚它是否会改善临床结果，是否与不可接受的毒性相关，或增加耐药微生物的获得率。在一项解决这些问题的持续努力中，患有CF1至12岁的幼儿将在全国60个临床中心之一登记参加为期18个月的临床试验，其中将包括大约300名儿童。这项临床试验旨在对首次从呼吸道培养中分离出PA的年轻CF患者进行吸入和口服抗伪瘤治疗的早期干预的随机对照评估。临床试验将研究两种不同的抗菌治疗方案：(1)以培养为基础的抗生素治疗，即根据PA阳性呼吸道培养的微生物学结果进行治疗；(2)循环抗生素治疗，即每季度有系统地提供治疗，直至18个月的研究期结束。吸入妥布霉素和口服环丙沙星已被选为本次试验的首选抗菌药，这是基于一次协商一致的会议，会上根据可获得的证据和安全数据选择了治疗方法并进行了排序。 临床试验的主要结果是在18个月的研究期间，将被分配到基于培养的治疗组的参与者与被分配到周期治疗组的参与者进行比较，得出复发的PA阳性培养的比例。另一项关键的临床结果指标将评估肺恶化发生的时间。次要结果将评估抗生素治疗对安全性的影响(不良事件概况，特别涉及肌肉骨骼症状、通过血清肌酐、听力、肝功能测试和完整血细胞计数衡量的肾功能)；临床变量(18个月内住院的情况、肺部恶化患者的比例、直线增长、体重增加、FEV1和总住院天数)；微生物学结果(通过菌落形态鉴定的粘液型PA菌株的存在和模式、口咽培养的PA菌株的MIC变化，以及从基线到研究结束的PA菌株的基因变化)；和PA血清学(针对外毒素A和其他选定的假单胞菌抗原的抗假单胞菌抗体滴度的变化和模式)。 从本质上讲，这项研究将提供有价值的临床和微生物学疗效和安全性数据，了解抗肿瘤药物治疗在儿童CF中的应用，为PA定植对后续健康状况的影响提供重要数据，并将提供有关下呼吸道感染的替代标记物的信息。

DESCRIPTION (provided by applicant): The purpose of this study is to determine a safe, effective, and systematic approach for the treatment of first isolation of Pseudomonas aemginosa (Pa) from young children with Cystic Fibrosis (CF). There is significant interest in investigating anti-pseudomonal therapies in very young children with the long-term goal of delaying or preventing chronic infection that contributes to irreversible lung disease. There has been minimal evaluation of the long-term clinical and microbiologic efficacy or safety of aggressive early intervention (i.e., intervention based on first isolation of Pa alone, in the absence of symptoms). While anti-pseudomonal therapy for first isolation of Pa will likely result in short-term eradication of Pa from respiratory cultures, it is not known whether it will improve clinical outcomes, be associated with unacceptable toxicities, or increase the rate of acquisition of resistant organisms. In an ongoing effort to address these issues, young children with CF ranging in age from 1 to 12 years will be enrolled at one of 60 clinical centers nationwide in an 18-month clinical trial that will include approximately 300 children. The clinical trial is designed to allow randomized controlled evaluation of early intervention with inhaled and oral antipseudomonal therapy in young patients with CF at first isolation of Pa from respiratory cultures. The clinical trial will investigate two different antimicrobial treatment regimens: (1) Culture-based antibiotic therapy, i.e., treatment based on microbiology findings of Pa positive respiratory cultures, and (2) Cycled antibiotic therapy, i.e., treatment provided systematically in quarterly cycles until the end of the 18-month study period. Inhaled tobramycin and oral ciprofloxacin have bean selected as first choice antimicrobials for this trial, based on a consensus conference at which therapies were selected and ranked based on the amount of evidence and of safety data available. The primary outcome of the clinical trial is the proportion of recurrent Pa positive cultures during the 18-month study period, comparing participants assigned to the culture-based treatment group with participants assigned to the cycled treatment group. Another key clinical outcome measure will evaluate the time to occurrence of a pulmonary exacerbation. The secondary outcomes will evaluate the effect of antibiotic therapy on safety (adverse events profile with particular reference to musculo-skeletal symptoms, renal function as measured by serum creatinine, hearing acuity, liver function tests, and complete blood count); clinical variables (occurrence of hospitalization during 18 months, proportion of patients with pulmonary exacerbations, linear growth, weight gain, FEV1, and total inpatient days); microbiology findings (presence and pattern of mucoid Pa isolates identified by colony morphology, changes in MICs of Pa isolates from oropharyngeal cultures, and changes in the genotype of Pa isolates from baseline to the end of the study); and Pa serology (changes in and patterns of anti-pseudomonal antibody titers against Exotoxin A and other selected pseudomonas antigens). In essence, this study will provide valuable clinical and microbiologic efficacy and safety data regarding the use of antipseudomonal therapy in young children with CF, will provide important data on the effect of PA colonization on subsequent health status, and will provide information on surrogate markers of lower airway infection.