A prospective trial of oral azithromycin when added to inhaled tobramycin in CF

 描述（由申请人提供）：囊性纤维化（CF）治疗的进展主要通过额外的治疗和药物实现。长期口服阿奇霉素和吸入妥布霉素是两种重要的药物，在共识的治疗指南中得到了铜绿假单胞菌（P.a.）CF患者的强烈支持。呼吸道感染绝大多数CF患者最终发展为P.a.慢性气道感染;因此，超过一半的CF患者可能长期接受阿奇霉素和吸入性妥布霉素的联合治疗。在过去15年的临床试验中，吸入妥布霉素的有益作用显著降低，但没有明确的解释。这与口服阿奇霉素的引入和快速纳入治疗方案是平行的。我们最近的临床前和临床研究强烈表明，阿奇霉素可以抑制妥布霉素的抗假单胞菌作用，与吸入治疗的临床反应差有关。通过注册查询，我们发现在美国75%的CF患者处方吸入妥布霉素，现在也处方阿奇霉素。因此，对于CF研究和临床护理界来说，确定阿奇霉素是否抑制了先前观察到的吸入妥布霉素对P.a.患者的健康益处至关重要。呼吸道感染通过一项在CF受试者中继续循环吸入妥布霉素的双盲、随机、安慰剂对照、交叉停药研究，我们将检测阿奇霉素联合吸入妥布霉素治疗的影响。我们的主要结果是吸入妥布霉素4周后FEV1的变化，比较吸入妥布霉素联合阿奇霉素与安慰剂的变化。在相同的两个阶段比较的次要结局指标将包括：患者报告的生活质量和痰P.a.细菌密度 探索性结局将包括需要研究方案外抗生素的时间和安全性。这项由经验丰富的研究人员团队和CF国家数据协调中心开发的多中心研究将产生必要的数据，以支持阿奇霉素和吸入性妥布霉素联合治疗的持续广泛实践，或考虑改变超过一半CF患者的护理建议的明确理由。它也将为未来的临床 联合抗生素治疗的临床试验，并为正在进行的和未来的机制研究提供了重要支持。

 DESCRIPTION (provided by applicant): Advances in cystic fibrosis (CF) treatment have been realized largely through additional treatments and medications. Chronic oral azithromycin and inhaled tobramycin are two important medications strongly supported in consensus treatment guidelines for CF patients with P. aeruginosa (P.a.) airway infection. The large majority of people with CF eventually develop chronic airway infection with P.a.; therefore, over half of all patients with CF will likely be prescribed concomitant azithromycin and inhaled tobramycin, chronically. The beneficial effects of inhaled tobramycin have significantly decreased in clinical trials over the last 15 years without clear explanation. This parallels the introduction and rapid incorporation of oral azithromycin into treatment regimens. Our recent preclinical and clinical research strongly suggests that azithromycin can inhibit the anti-pseudomonal effects of tobramycin, associating with poor clinical response to inhaled therapy. Through registry query, we find that 75% of CF patients in the US who are prescribed inhaled tobramycin are also now prescribed azithromycin. It is therefore critically important to the CF research and clinical care community to definitively determine if azithromycin inhibits the previously observed health benefits of inhaled tobramycin in patients with P.a. airway infection. Through a double-blinded, randomized, placebo-controlled, crossover withdrawal study of azithromycin in CF subjects who continue cycled, inhaled tobramycin, we will test the impact of combining azithromycin with inhaled tobramycin therapy. Our primary outcome will be the change in FEV1 in response to 4 weeks of inhaled tobramycin, comparing a period of combination of inhaled tobramycin with azithromycin vs. placebo. Secondary outcome measures compared during the same two periods will include: change in patient reported quality of life and sputum P.a. bacterial density. Exploratory outcomes will include time to need antibiotics outside of study protocol and safety. This multi-center study, developed by an experienced team of investigators and the CF national data coordinating center, will generate necessary data to either support the ongoing widespread practice of combined azithromycin and inhaled tobramycin, or definitive reason to consider changing care recommendations for over half of all CF patients. It will also inform future clinical trials with combination antibiotic therapy and critically support ongoing and future mechanistic research.