Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS) - CCC - Lead Application

描述（由申请人提供）： 囊性纤维化（CF）患者患病和死亡的主要原因是进行性肺部疾病。CF是由氯离子通道基因突变引起的。与潜在的氯离子通道异常相关的气道粘液清除缺陷使CF患者易于发生慢性气道感染和炎症，这反过来又导致进行性气道损伤。现在已经确定CF肺病开始于婴儿期，通常在症状发作之前，这为早期干预提供了依据。短期研究显示吸入高渗盐水（HS）可改善6岁以上CF患者的粘膜纤毛清除率，长期研究显示吸入HS可改善6岁以上CF患者的肺功能、降低肺加重率并改善生活质量。没有年轻CF患者的疗效数据。HS是在婴儿中研究的特别有吸引力的药物，因为它改善了有缺陷的粘膜纤毛清除，这是导致CF肺病的级联事件中的早期步骤，预计在气道感染和炎症发作之前是异常的。本提案是一项随机对照试验，旨在评估入组时4至15个月CF婴儿每日两次吸入7% HS持续48周的疗效和安全性。我们的主要假设是，与对照剂（等渗盐水）相比，HS将改善婴儿肺功能测试测量的过度充气和阻塞性肺病。拟议试验产生的疗效和安全性结果可能首次为早期开始广泛用于老年CF患者的治疗提供证据，从而可能在其变得不可逆之前延迟或预防毁灭性的气道损伤。将在16个中心招募150名4至15个月的婴儿。研究访视将在入组时以及第4、12、24、36和48周进行，通常与常规CF诊所访视同时进行。受试者将在入组时、第24周和第48周接受肺功能检查。主要终点是从基线到治疗结束时功能残气量的变化，这是一种过度充气的指标。还将评估其他肺功能指标。次要终点是至首次需要抗生素治疗的肺部急性加重的时间。其他临床终点将包括体重和身高的变化、静息呼吸频率和血氧测定、标准化咳嗽评分和父母家庭报告的症状。将通过评价不良事件发生率、退出、治疗依从性、从呼吸道培养物中新分离出CF病原体;以及48周治疗期间研究访视时测量的临床参数来评估安全性。本临床协调中心申请与数据协调中心申请一起提交。这是铅应用程序。本研究的公共卫生影响可能是显著的，因为它可能提供高渗盐水在CF婴儿中的首次疗效和长期安全性数据，可能允许在最年轻的CF患者中使用这种有前途的药物。HS是在婴儿中研究的特别有吸引力的药物，因为它改善了有缺陷的粘膜纤毛清除，这是导致CF肺病的级联事件中的早期步骤，预计在气道感染和炎症发作之前是异常的。这将是第一个专门针对CF婴儿的肺部维持治疗的多中心临床试验，也是第一个使用婴儿肺功能作为终点的试验。

DESCRIPTION (provided by applicant): The primary cause of illness and death in patients with cystic fibrosis (CF) is progressive lung disease. CF is caused by a mutation in a chloride channel gene. Defective clearance of airway mucus related to the underlying chloride channel abnormality predisposes patients with CF to chronic airway infection and inflammation which in turn causes progressive airway damage. It is now well established that CF lung disease begins in infancy, frequently prior to the onset of symptoms, providing a rationale for early intervention. Inhaled hypertonic saline (HS) has been shown in short-term studies to improve mucociliary clearance and in long term studies to improve lung function, decrease the rate of pulmonary exacerbations and improve quality of life in CF patients over 6 years of age. There are no efficacy data in younger CF patients. HS is a particularly attractive agent to study in infants because it improves defective mucociliary clearance, an early step in the cascade of events leading to CF lung disease that is expected to be abnormal prior to the onset of airway infection and inflammation. This proposal is for a randomized, controlled trial to assess the efficacy and safety of 7% HS inhaled twice daily for 48 weeks among infants with CF 4 to 15 months of age at enrollment. Our primary hypothesis is that, compared to the control agent (isotonic saline), HS will improve hyperinflation and obstructive lung disease as measured by infant lung function testing. The efficacy and safety results generated by the proposed trial may for the first time provide evidence for early initiation of a therapy used widely in older CF patients, thereby potentially delaying or preventing devastating airway damage before it becomes irreversible. One hundred and fifty infants ages 4 to 15 months will be enrolled at 16 centers. Study visits will take place at enrollment and weeks 4, 12, 24, 36 and 48, generally in conjunction with routine CF clinic visits. Subjects will undergo lung function testing at enrollment, 24 and 48 weeks. The primary endpoint is the change in the functional residual capacity, a measure of hyperinflation, from baseline to end of treatment. Additional lung function measures will also be assessed. The secondary endpoint is the time to first pulmonary exacerbation requiring antibiotic therapy. Other clinical endpoints will include changes in weight and height, resting respiratory rate and oximetry, a standardized cough score, and symptoms by parental home report. Safety will be assessed by evaluation of rates of adverse events, withdrawal, adherence to treatment, new isolation of CF pathogens from respiratory cultures; and clinical parameters measured at study visits during the 48-week treatment period. This Clinical Coordinating Center application is submitted in conjunction with a Data Coordinating Center application. This is the lead application. The public health impact of this study could be significant, as it may provide the first efficacy and long term safety data on hypertonic saline in infants with CF, potentially allowing the use of this promising agent in the youngest CF patients. HS is a particularly attractive agent to study in infants because it improves defective mucociliary clearance, an early step in the cascade of events leading to CF lung disease that is expected to be abnormal prior to the onset of airway infection and inflammation. This would be the first multicenter clinical trial of a pulmonary maintenance therapy specifically in infants with CF, and the first to use measures of infant lung function as an endpoint.