Clinical study of aerosolized KL4 surfactant for neonatal RDS and BPD prevention

 描述（由申请人提供）：Discovery Laboratories，Inc.（Discovery）正在开发一种新型的药物-器械联合疗法AEROSURF（r），该疗法采用优化的专有毛细血管气雾剂发生器（CAG），将雾化表面活性剂（lucinactant）输送给患有呼吸窘迫综合征（RDS）或有呼吸窘迫综合征风险的早产儿，这些早产儿随后可能患上称为支气管肺发育不良（BPD）的慢性肺病。Lucinactant（SURFAXIN（r）Intraperitoneal Suspension）是Discovery Labs专有的合成表面活性剂，含有KL 4肽，于2012年获得美国FDA批准用于预防早产儿RDS的气管内给药。该拨款提案是作为授予Discovery的SBIR快速通道拨款的后续申请提交的。第一阶段支持开发一种用于雾化lucinactant的临床可用CAG装置。II期资助了一项已完成的2a期初步临床研究，该研究在患有RDS并有发生BPD风险（NHLBI RFA针对的疾病区域）的早产儿中进行，这些早产儿接受了鼻持续气道正压通气（nCPAP）。BPD在小于32周胎龄的早产儿中的发生率超过30%，并且是一种与显著死亡率和长期发病率相关的非常昂贵的疾病。RDS的主要治疗是表面活性物质替代疗法（SRT）和机械通气（MV）。SRT目前需要通过气管内导管（ETT）进行气管内滴注，以有效输送至肺部。尽管ETT插管、MV和SRT可以挽救生命，但它们与医源性并发症相关，包括气道创伤、感染风险增加以及体积和气压创伤，所有这些都与BPD的发展有关。为了避免这些后遗症，nCPAP越来越多地用于支持呼吸功能不全的早产儿。然而，使用nCPAP通常会使早产儿无法接受SRT，这些婴儿中有一半随后需要插管、晚期表面活性剂治疗和机械通气，增加了BPD的风险。迄今为止，在使用现有气溶胶发生装置的表面活性剂的非ETT递送中取得的成功有限，因此我们开发了AEROSURF。我们计划在接受nCPAP治疗的早产儿中开展一项更大规模（n=~240）的随访研究，以评估气雾化Lucinactant（AEROSURF）的安全性，并评估药物-器械组合产品在预防nCPAP失败方面的有效性，并将降低重度RDS和BPD的发生率作为关键结局。具体而言，我们将根据2a期临床研究的结果，对两种剂量的AEROSURF进行一项多中心、随机、开放标签的2b期临床研究。结局将侧重于安全性（严重不良事件和器械不良事件）和有效性;后者将主要通过治疗失败的发生率进行评估。次要疗效指标将包括氧合改善和呼吸机支持需求减少（将在72小时内进行评估）。出生后7天和28天），以及36周PMA时BPD的发生率;还计划对婴儿进行随访，直至1岁校正年龄。

 DESCRIPTION (provided by applicant): Discovery Laboratories, Inc. (Discovery) is developing a novel drug-device combination therapy, AEROSURF(r) that employs an optimized proprietary capillary aerosol generator (CAG) to deliver aerosolized surfactant (lucinactant) to preterm infants with or at risk for respiratory distress syndrome (RDS) and who may subsequently develop a chronic lung disease known as bronchopulmonary dysplasia (BPD). Lucinactant (SURFAXIN(r) Intratracheal Suspension) is Discovery Labs' proprietary, synthetic, KL4 peptide-containing surfactant that was approved by the US FDA in 2012 for endotracheal administration for the prevention of RDS in preterm infants. This grant proposal is being submitted as follow-on to an SBIR Fast-track grant awarded to Discovery. Phase I supported the development of a clinic-ready CAG device for aerosolization of lucinactant. Phase II funded a completed Phase 2a pilot clinical study in preterm infants on nasal continuous positive airway pressure (nCPAP) with RDS and at risk for developing BPD (disease areas targeted by the NHLBI RFAs). BPD occurs in excess of 30 percent in preterm infants below 32 weeks gestation age, and is a very costly disease associated with significant mortality and long-term morbidity. The primary therapy for RDS is surfactant replacement therapy (SRT) and mechanical ventilation (MV). SRT currently requires intratracheal instillation via an endotracheal tube (ETT) for effective delivery to the lung. Although ETT intubation, MV and SRT are lifesaving, they are associated with iatrogenic complications include airway trauma, increased the risk of infection, and volu- and baro-trauma, all of which have been implicated in the development of BPD. In order to avoid these sequelae, nCPAP is increasingly being used to support preterm infants with respiratory insufficiency. However, use of nCPAP typically precludes preterm infants from receiving SRT, and half of these infants subsequently require intubation, late surfactant therapy, and mechanical ventilation, increasing the risk for BPD. Limited success has been achieved to date in non-ETT delivery of surfactants with existing aerosol generating devices, thus our development of AEROSURF. We plan to evaluate aerosolized lucinactant (AEROSURF) in a larger (n=~240) follow-on study in preterm infants on nCPAP to establish safety and to estimate effectiveness of the drug-device combination product in preventing nCPAP failure, and reducing the incidence of severe RDS and BPD as key outcomes. Specifically, we will conduct a multicenter, randomized, open-label Phase 2b clinical study of two doses of AEROSURF, that are based on outcomes from the phase 2a clinical study. Outcomes will focus on safety (serious adverse events and adverse device events) and efficacy; the later will be assessed primarily by the incidence of treatment failure. Secondary efficacy measures will include improvements in oxygenation and reduction in need for ventilator support (to be assessed through 72 hrs. 7 and 28 days after birth), as well as the incidence of BPD at 36 weeks PMA; follow-up of infants through 1-year corrected age is also planned.