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，系统的方法来治疗首次分离的铜绿假单胞菌（Pa）从幼儿囊性纤维化（CF）。 在非常年幼的儿童中研究抗假单胞菌治疗具有延缓或预防导致不可逆肺部疾病的慢性感染的长期目标，这是非常重要的。对积极早期干预的长期临床和微生物学疗效或安全性的评价很少（即，在没有症状的情况下，基于第一次单独分离Pa的干预）。虽然首次分离Pa的抗假单胞菌治疗可能导致从呼吸道培养物中短期根除Pa，但尚不清楚其是否会改善临床结局、与不可接受的毒性相关或增加耐药微生物的获得率。为了解决这些问题，将在全国60个临床中心之一招募1至12岁的CF幼儿，进行为期18个月的临床试验，其中将包括约300名儿童。临床试验的目的是允许随机对照评价早期干预与吸入和口服抗假单胞菌治疗的年轻患者CF在第一次分离Pa从呼吸道培养。临床试验将研究两种不同的抗菌治疗方案：（1）基于培养的抗生素治疗，即，基于Pa阳性呼吸道培养物的微生物学结果的治疗，和（2）循环抗生素治疗，即，以季度为周期系统性提供治疗，直至18个月研究期结束。吸入妥布霉素和口服环丙沙星已被选为本试验的首选抗菌药物，这是基于一次共识会议，在该会议上，根据证据量和可用的安全性数据选择和排名治疗方法。 临床试验的主要结果是18个月研究期间复发性Pa阳性培养物的比例，比较分配到基于培养物的治疗组的参与者与分配到循环治疗组的参与者。另一项关键临床结局指标将评价至发生肺部急性加重的时间。次要结局将评价抗生素治疗对安全性的影响（不良事件概况，特别是肌肉骨骼症状、通过血清肌酸酐测量的肾功能、听力、肝功能检查和全血细胞计数）;临床变量（18个月内住院的发生率，肺部恶化的患者比例，线性生长，体重增加，FEV 1，和总住院日）;微生物学结果（通过菌落形态学鉴定的粘液样Pa分离株的存在和模式、来自口咽培养物的Pa分离株MIC的变化以及Pa分离株基因型从基线至研究结束的变化）;和Pa血清学（抗外毒素A和其它选择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，关于使用抗假单胞菌治疗幼儿CF，将提供重要的数据，PA定植的影响，随后的健康状况，并将提供下呼吸道感染的替代标志物的信息。

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.