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

雾化KL4表面活性剂预防新生儿RDS和BPD的临床研究

• 批准号: 9095500
• 负责人: Robert Segal
• 金额: $ 100万
• 依托单位: WINDTREE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095500
• 关键词: Address; Aerosols; Age; Animals; Applications Grants; Area; Award; Birth; Blood capillaries; Breathing; Bronchopulmonary Dysplasia; Chemical Surfactants; Chronic lung disease; Clinic; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Complication; Data; Development; Devices; Disease; Dose; Dysplasia; Effectiveness; Event; Failure; Funding; Funding Opportunities; Gestational Age; Grant; Health; Hour; Incidence; Infant; Infection; Intratracheal Intubation; Intubation; Investigational New Drug Application; Laboratories; Life; Lung; Lung diseases; Marketing; Masks; Measures; Mechanical ventilation; Mission; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Outcome; Peptides; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Population; Pregnancy; Premature Infant; Prevention; Randomized; Respiratory Failure; Respiratory Insufficiency; Risk; Safety; Serious Adverse Event; Small Business Innovation Research Grant; Surfactant therapy; Suspension substance; Suspensions; Technology; Testing; Therapeutic; Trauma; Treatment Failure; Tube; Ventilator; aerosolized; base; capillary; commercialization; cost; design; endotracheal; follow-up; meetings; mortality; nCPAP Ventilation; neonatal respiratory distress; neonate; novel; novel therapeutics; open label; premature; prevent; programs; public health relevance; respiratory distress syndrome; success; surfactant; surfactant replacement therapy; therapy development

 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.

 描述（由申请人提供）：Discovery Laboratories, Inc.（Discovery）正在开发一种新型药物设备组合疗法 AEROSURF(r)，该疗法采用优化的专有毛细管气雾发生器 (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剂（lucinactant），这些早产儿随后可能会患上称为慢性肺病的疾病。 支气管肺发育不良（BPD）。 Lucinactant (SURFAXIN(r) Intracheal Suspension) 是 Discovery Labs 专有的、合成的、含 KL4 肽的表面活性剂，于 2012 年获得美国 FDA 批准用于气管内给药，以预防早产儿 RDS。该拨款提案是作为授予 Discovery 的 SBIR 快速拨款的后续拨款而提交的。第一阶段支持开发临床就绪的 CAG 装置，用于雾化 lucinactant。 II 期资助了一项已完成的 2a 期试点临床研究，对象是患有 RDS 且有发展为 BPD（NHLBI RFA 所针对的疾病领域）风险的早产儿，进行经鼻持续气道正压通气 (nCPAP)。 BPD 发生在 32 周以下早产儿中的比例超过 30%，并且是一种代价高昂的疾病，具有显着的死亡率和长期发病率。 RDS 的主要治疗方法是表面活性剂替代疗法 (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，以有效输送至肺部。虽然 ETT 插管、MV 和 SRT 可以挽救生命，但它们与医源性并发症相关，包括气道损伤、感染风险增加以及体积和气压损伤，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 通常会妨碍早产儿接受 SRT，其中一半婴儿随后需要插管、晚期表面活性剂治疗和机械通气，从而增加了 BPD 的风险。迄今为止，在使用现有气溶胶发生装置进行表面活性剂的非 ETT 输送方面取得的成功有限，因此我们开发了 AEROSURF。我们计划在一项针对早产儿 nCPAP 的更大规模 (n=~240) 后续研究中评估雾化 lucinactant (AEROSURF)，以确定安全性并评估该药物-器械组合产品在预防 nCPAP 失败方面的有效性，以及降低严重 RDS 和 BPD 的发生率作为关键结局。具体来说，我们将根据 2a 期临床研究的结果，对两种剂量的 AEROSURF 进行多中心、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器械事件）和有效性；后者主要通过治疗失败的发生率来评估。次要疗效指标包括改善氧合和减少呼吸机支持需求（通过出生后 7 天和 28 天 72 小时进行评估），以及 PMA 36 周时 BPD 的发生率；还计划对婴儿进行一岁校正年龄的随访。