Phase 2 Clinical Trial Evaluating a Novel Therapy in Patients who are Post-lung Transplant

评估肺移植后患者新疗法的 2 期临床试验

基本信息

批准号：
10205169
负责人：
Daniel W. Copeland
金额：
$ 87.06万
依托单位：
RENOVION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205169
关键词：
Advanced Development Adverse event Ascorbic Acid Authorization documentation Awareness Bacteria Bilateral Bronchiectasis Bronchiolitis Obliterans Caring Cessation of life Chemicals Chronic Chronic Obstructive Airway Disease Chronic lung disease Clinical Clinical Data Clinical Research Clinical Trials Data Monitoring Committees Control Groups Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Disease Progression Educational Materials Educational process of instructing Ensure Environment FDA approved Formulation Functional disorder Graft Rejection Growth Health Immunosuppression Impairment In Vitro Infection Inflammation Inhalation Innovative Therapy Institutional Review Boards Intervention Ion Transport Irritants Lead Legal patent Lung Lung Transplantation Lung diseases Marketing Measures Mediating Monitor Morbidity - disease rate Mucous body substance Multi-Institutional Clinical Trial Nebulizer Ophthalmology Organ Transplantation Orphan Drugs Pathology Patient Education Patient Recruitments Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Physicians Pilot Projects Plasma Prognosis Pulmonary Function Test/Forced Expiratory Volume 1 Quality of life Randomized Recommendation Reporting Research Personnel Resources Respiratory System Risk Safety Scientist Site Small Business Innovation Research Grant Solid Spirometry Survival Rate Syndrome Testing Therapeutic Therapeutic Agents Therapeutic immunosuppression Time Transplant Recipients Transplantation Transplanted Lung Complication Viscosity Work clinical practice commercialization design graft failure high risk improved lung allograft mortality novel therapeutic intervention novel therapeutics patient population phase 1 study post-transplant pre-clinical preclinical study prevent prospective pulmonary function pulmonary function decline recruit retention rate skills standard of care success treatment group

项目摘要

Chronic lung allograft dysfunction (CLAD) is the primary cause of mortality in lung transplant recipients beyond one year of transplant and includes bronchiolitis obliterans syndrome (BOS). Currently, there are no therapeutic agents available to prevent CLAD or BOS. Treatments are limited to supportive strategies with low and variable success rates once CLAD develops. ARINA-1, a patented formulation for a nebulized therapy of ascorbic acid (ASC), is designed to use when patients develop precursors to BOS, known as BOS-0p, rather than wait until it progresses to potentially unrecoverable pathology. As a patient develops BOS-0p, the physical and chemical barriers that typically maintain pulmonary health are compromised, making the lung more susceptible to irritants and bacteria in the environment. This initiates a cycle of inflammation and infection that leads to decreased pulmonary function and, ultimately, graft rejection and failure. ASC is critical to first-line airway defenses and is significantly depleted in the airway of patients who are post lung transplant. Thus, the mechanism of ARINA-1 therapy is simple: ARINA-1 delivers ASC directly to the lung, which restores the first lines of defense against inflammation and infection. In preclinical studies, we demonstrate that ARINA-1 both activates CFTR-mediated ion transport and mucus transport, decreases mucus viscosity and inflammation, and inhibits bacterial growth. Pilot studies in three patients with severe pulmonary disease demonstrate ARINA-1 safety and preliminary efficacy. A successful Phase 1 study in stable lung transplant patients confirmed ARINA-1 safety and prompted the FDA to permit an NDA-enabling Phase 2 clinical trial in patients with BOS-0p. The Aims of this proposal are designed to advance ARINA-1 to FDA approval for use in lung transplant patients with BOS-0p, for whom there are no current therapies. In this Direct-to-Phase II submission, we will conduct the NDA-enabling multi-center clinical trial to rigorously evaluate ARINA-1 efficacy in BOS-0p. The successful completion of these Aims will result in NDA filing for the first FDA-approved therapy for lung transplant patients with BOS-0p to prevent the progression to CLAD and graft failure. ARINA-1 approval will improve clinical practice for lung transplant care, by offering physicians a therapeutic option for treating BOS-0p before it progresses to CLAD, increasing not only survival, but also quality of life during the prolonged survival.

慢性同种异体肺移植功能障碍（CLAD）是肺移植受者死亡的主要原因移植一年，包括闭塞性细支气管炎综合征 (BOS)。目前尚无治疗方法可用于预防 CLAD 或 BOS 的药物。治疗仅限于低且可变的支持策略 CLAD 发展后的成功率。 ARINA-1，抗坏血酸雾化疗法的专利配方 (ASC)，旨在当患者出现 BOS 前体（称为 BOS-0p）时使用，而不是等到它出现进展为可能无法恢复的病理。当患者出现 BOS-0p 时，物理和化学反应通常维持肺部健康的屏障受到损害，使肺部更容易受到刺激物以及环境中的细菌。这会引发炎症和感染的循环，从而导致减少肺功能，最终导致移植物排斥和失败。 ASC 对于一线气道防御至关重要，并且肺移植后患者气道中的气道显着减少。因此，ARINA-1的机制治疗方法很简单：ARINA-1 将 ASC 直接输送到肺部，从而恢复抵抗病毒的第一道防线炎症和感染。在临床前研究中，我们证明 ARINA-1 既能激活 CFTR 介导的离子运输和粘液运输，降低粘液粘度和炎症，并抑制细菌生长。对三名患有严重肺部疾病的患者进行的初步研究证明了 ARINA-1 的安全性和初步结果功效。在稳定的肺移植患者中进行的一项成功的 1 期研究证实了 ARINA-1 的安全性并提示 FDA 允许对 BOS-0p 患者进行 NDA 2 期临床试验。该提案的目标是旨在推动 ARINA-1 获得 FDA 批准用于 BOS-0p 肺移植患者，对于这些患者来说目前尚无治疗方法。在这次直接进入第二阶段的提交中，我们将进行 NDA 支持的多中心严格评估 ARINA-1 在 BOS-0p 中的疗效的临床试验。这些目标的成功实现将导致第一个 FDA 批准的治疗 BOS-0p 肺移植患者的新药申请 (NDA) 申请，以预防进展为 CLAD 和移植失败。 ARINA-1 的批准将改善肺移植护理的临床实践，通过在 BOS-0p 进展为 CLAD 之前为医生提供治疗选择，不仅增加了生存，还包括延长生存期间的生活质量。