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

描述(由申请人提供)： 囊性纤维化患者的主要疾病和死亡原因是进行性肺部疾病。慢性阻塞性肺疾病是由氯通道基因突变引起的。与潜在的氯离子通道异常相关的呼吸道粘液清除缺陷使CF患者易于发生慢性呼吸道感染和炎症，进而导致进行性呼吸道损害。现在公认的是，慢性肺病在婴儿期就开始了，通常在症状出现之前，这为早期干预提供了理论依据。吸入高渗盐水(HS)已在短期研究中被证明可以改善粘膜纤毛清除，在长期研究中被证明可以改善肺功能，降低肺恶化的发生率，并改善6岁以上的CF患者的生活质量。目前还没有年轻的CF患者的疗效数据。HS是一种特别吸引婴儿研究的药物，因为它改善了有缺陷的粘液纤毛清除，这是导致CF肺部疾病的一连串事件中的早期步骤，预计在呼吸道感染和炎症发生之前，该疾病将是异常的。这项建议是一项随机对照试验，以评估在登记时患有CF4至15个月的婴儿每天两次吸入7%HS的疗效和安全性，持续48周。我们的基本假设是，与对照组(等渗盐水)相比，HS将改善婴儿肺功能测试所测量的恶性通货膨胀和阻塞性肺疾病。拟议中的试验产生的有效性和安全性结果可能首次为早期开始在老年CF患者中广泛使用的治疗提供证据，从而潜在地在其不可逆转之前延迟或防止毁灭性的气道损伤。150名4至15个月大的婴儿将在16个中心登记。学习访问将在注册时和第4、12、24、36和48周进行，通常与常规的CF诊所访问一起进行。受试者将在登记时、24周和48周接受肺功能测试。主要终点是从基线到治疗结束时功能性剩余容量的变化，这是一种衡量恶性通货膨胀的指标。还将评估其他肺功能指标。次要终点是首次肺部恶化需要抗生素治疗的时间。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仪，标准化的咳嗽评分，以及父母家庭报告的症状。安全性将通过评估不良事件、停药、坚持治疗、从呼吸道培养中分离出新的CF病原体以及在48周治疗期间的研究访问中测量的临床参数来评估。此临床协调中心申请与数据协调中心申请一起提交。这是主要的应用程序。这项研究对公众健康的影响可能是重大的，因为它可能提供高渗盐水在患有CF的婴儿中的首次有效性和长期安全性数据，并有可能使这种有希望的药物应用于最年轻的CF患者。HS是一种特别吸引婴儿研究的药物，因为它改善了有缺陷的粘液纤毛清除，这是导致CF肺部疾病的一连串事件中的早期步骤，预计在呼吸道感染和炎症发生之前，该疾病将是异常的。这将是第一个专门针对患有CF的婴儿进行的肺维持疗法的多中心临床试验，也是第一个将婴儿肺功能测量作为终点的试验。

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.