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

 描述(由申请人提供)：Discovery实验室公司(DISCOVERY)正在开发一种新型药物-设备组合疗法AEROSURF(R)，它使用经过优化的专有毛细管气溶胶发生器(CAG)向患有呼吸窘迫综合征(RDS)或有呼吸窘迫综合征(RDS)风险的早产儿输送雾化表面活性物质(LUCINACTIVE)，这些早产儿随后可能发展为一种称为支气管肺发育不良(BPD)的慢性肺部疾病。Lucinacant(SURFAXIN(R)气管内混悬剂)是Discovery Labs的专利合成KL4多肽表面活性剂，于2012年被美国FDA批准用于气管内给药，以预防早产儿RDS。这项赠款提案是作为授予发现号的SBIR快速通道赠款的后续项目提交的。第一阶段支持开发一种临床上可供临床使用的荧光素雾化CAG设备。第二阶段资助了一项完成的2a阶段试点临床研究，用于早产儿鼻腔持续气道正压(NCPAP)合并RDS并有患BPD(NHLBI RFA目标病区)的风险。BPD在胎龄32周以下的早产儿中发生率超过30%，是一种与重大死亡率和长期发病率相关的非常昂贵的疾病。RDS的主要治疗方法是肺表面活性物质替代疗法(SRT)和机械通气(MV)。目前，SRT需要通过气管内导管(ETT)进行气管内滴注，以有效地将药物输送到肺部。尽管ETT插管、MV和SRT是救命的，但它们与医源性并发症有关，包括呼吸道损伤、感染风险增加、容量和气压创伤，所有这些都与BPD的发生有关。为了避免这些后遗症，NCPAP越来越多地被用于支持早产儿呼吸功能不全。然而，使用nCPAP通常会阻止早产儿接受SRT，这些早产儿中有一半随后需要插管、晚期肺表面活性物质治疗和机械通气，增加了BPD的风险。到目前为止，利用现有的气溶胶发生装置在非ETT输送表面活性剂方面取得了有限的成功，因此我们开发了AEROSURF。我们计划在一项更大的(n=~240)早产儿NCPAP的后续研究中评估雾化Lucinactive(AEROSURF)，以确定安全性，并评估药物-装置组合产品在预防NCPAP失败和减少严重RDS和BPD的发生率方面的有效性。具体地说，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。结果将侧重于安全性(严重不良事件和不良设备事件)和疗效；后者将主要通过治疗失败的发生率进行评估。二级疗效措施将包括改善氧合和减少对呼吸机支持的需求(通过72小时进行评估)。出生后7天和28天)，以及产后36周BPD的发生率；还计划对婴儿进行1岁校正年龄的跟踪调查。

 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.