Phase 2 Study of Intravenous Gallium Nitrate in the Treatment of Cystic Fibrosis

描述(由申请人提供)： 一种新的抗感染方法是利用已经施加在体内入侵生物体上的压力。铁(Fe)代谢是感染细菌的一个关键弱点，因为生物体需要铁来生长。申请人提出，一种使用金属镓(Ga)来扰乱细菌铁代谢的策略有望成为一种抗菌方法。由于其化学上与铁相似，申请者指出，镓可以在许多生物系统中替代铁，并抑制铁依赖的过程。申请人已编制数据显示，镓杀死条件致病菌铜绿假单胞菌(包括抗生素耐药菌株)，对生物被膜具有活性，并治疗3种不同模型的铜绿假单胞菌感染。这些数据，硝酸镓(商标，Ganite)被FDA批准静脉(IV)给药的事实，以及开发中的新抗生素的缺乏向申请者表明，镓可能是治疗铜绿假单胞菌感染的一种有前途的新疗法。对慢性感染铜绿假单胞菌的囊性纤维化患者进行的初步1b期研究向申请人表明，静脉注射镓似乎是安全的，耐受性良好，具有良好的药代动力学特征，并与开始5天静脉注射镓14天和28天后临床上有意义的肺功能改善有关。申请人提出了一项概念验证第二阶段临床试验，以确认先前的疗效发现，并提供有关静脉注射镓在感染铜绿假单胞菌的囊性纤维化患者中的安全性和药代动力学的进一步数据。这项研究的具体目的是：1)评估接受5天连续静脉注射镓和安慰剂的囊性纤维化患者在第28天的肺功能反应率；以及2)与安慰剂相比，评估成人囊性纤维化受试者连续5天静脉注射镓的安全性和药代动力学。

DESCRIPTION (provided by applicant): A novel anti-infective approach is to exploit stresses already imposed on invading organisms in vivo. Iron (Fe) metabolism is a key vulnerability of infecting bacteria because organisms require iron for growth. The applicant proposed that a strategy using the metal gallium (Ga) to disrupt bacterial iron metabolism holds promise as an antimicrobial approach. Due to its chemical similarity to iron, the applicants state that gallium can substitute for iron in many biologic systems and inhibit iron-dependent processes. The applicant has complied data to show that gallium kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and treats 3 different models of Pseudomonas aeruginosa infections. These data, the fact that gallium nitrate (trade name, Ganite) is FDA approved for intravenous (IV) administration, and the dearth of new antibiotics in development indicate to the applicant that gallium could be a promising new therapeutic for Pseudomonas aeruginosa infections. An initial Phase 1b study in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa indicated to the applicant that IV gallium appeared to be safe, well tolerated, has a good pharmacokinetic profile, and is associated with a clinically meaningful improvement in lung function 14 days and 28 days after the start of a 5 day infusion of IV gallium. The applicant proposes a proof of concept Phase 2 clinical trial to confirm the prior findings of efficacy and provide further data regarding the safety and pharmacokinetics of IV gallium in cystic fibrosis subjects infected with Pseudomonas aeruginosa. The Specific Aims of the study are to: 1) assess the pulmonary function response rate at day 28 in cystic fibrosis patients receiving a 5-day continuous IV gallium and placebo; and 2) to assess the safety and pharmacokinetics of a 5 day continuous IV infusions of gallium in adult cystic fibrosis subjects compared to placebo.