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

 描述(申请人提供)：囊性纤维化(CF)治疗的进展主要是通过额外的治疗和药物实现的。慢性口服阿奇霉素和吸入妥布霉素是公认的铜绿假单胞菌(P.A.)CF患者治疗指南中强烈支持的两种重要药物。呼吸道感染。绝大多数慢性支气管炎患者最终发展为慢性呼吸道感染的P.A.；因此，超过一半的慢性支气管炎患者可能会同时服用阿奇霉素和吸入妥布霉素。在过去的15年里，在没有明确解释的情况下，临床试验中吸入妥布霉素的有益效果显著下降。这与口服阿奇霉素的引入和快速并入治疗方案是平行的。我们最近的临床前和临床研究有力地表明，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，我们发现在美国开了吸入性妥布霉素的CF患者中，75%的人现在也开了阿奇霉素。因此，明确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，这对CF研究和临床护理社区至关重要。呼吸道感染。通过一项双盲、随机、安慰剂对照、交叉停用阿奇霉素的研究，我们将测试阿奇霉素与吸入妥布霉素联合治疗的效果。我们的主要结果将是吸入妥布霉素4周后FEV1的变化，比较吸入妥布霉素、阿奇霉素和安慰剂的合并期。在相同的两个时期比较的次要结果指标将包括：患者报告的生活质量和痰P.A.的变化。细菌密度。 探索性结果将包括在研究方案和安全性之外需要抗生素的时间。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，以支持正在广泛使用的阿奇霉素和妥布霉素吸入剂的联合应用，或者产生明确的理由，考虑改变对超过一半的CF患者的治疗建议。它还将通知未来的临床 与抗生素联合治疗的试验和关键支持正在进行的和未来的机制研究。

 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.