A Phase Ib, Dose-finding and Pharmacodynamic Study of NVX-508 in Sickle Cell Disease Patients
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 主要终点
- Maximum tolerated dose of NVX-508
研究概览
简要总结
This Phase 1b study in adults with sickle cell disease (SCD) in steady-state (non-acutely ill) aims to evaluate safety and toxicity of NVX-508 in a multi-dosing paradigm as well as to determine the maximum tolerated dose (MTD) in this population. The information gained from this study will be used in making decisions about the appropriate dose(s) and dosing schedule in future multicenter studies of the efficacy of NVX-508 in the treatment of vaso-occlusive episodes (VOE).
详细描述
Sickle cell disease (SCD) is a genetic disorder of hemoglobin that affects millions of individuals worldwide, with sub-Saharan Africa bearing the greatest burden of disease. The leading causes of hospitalization and death in individuals with sickle cell disease are painful VOE (associated with tissue injury from reduced oxygen supply) and "acute chest syndrome" respectively. Acute chest syndrome (ACS) is a form of acute lung injury unique to SCD that arises de novo or during the course of painful VOE.
A safe, reliable therapeutic deployed early in the course of painful VOE (with or without ACS) that restores oxygen supply to tissues, could potentially attenuate tissue injury, resolve pain and improve patient outcomes.
NVX-508 is a liquid fluorocarbon which transports oxygen. Stoichiometrically, NVX-508 has 200 times the oxygen carrying capacity of human hemoglobin.Oxygen is taken up by NVX-508 as it circulates through the alveolar capillary bed in the lungs and is released in blood and tissues with low oxygen content. Consequently, if it were administered intravenously (IV) and passed through the lungs of patients, it would take up oxygen, increasing the oxygen concentration in blood in a dose-dependent manner and release it to tissues with low oxygen.
The active component of NVX-508 was originally developed as an ultrasound contrast agent. It has been tested as such in over 2200 patients to whom it was safely administered as a bolus IV injection.The pharmacokinetics of NVX-508 in humans exhibits a biphasic decline after an iv bolus dose; a rapid initial decline followed by a slow terminal phase. The terminal phase t1/2 (half- life) ranges from 81-99.5 min for doses of 0.15-0.35 ml/kg. NVX-508 is not metabolized in humans, it is removed from the body unchanged in the breath (expired air) .
The rationale for studying NVX-508 for SCD is based on data from preclinical studies in the mouse model of ACS. NVX-508 when used as rescue therapy in the mouse model, restored oxygen saturation to baseline in mice experiencing hypoxemia, with 100% survival. NVX-508 reduced pulmonary vascular congestion in SCD mice experiencing ACS.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Clinical diagnosis of SCD without acute VOE and/or ACS.
- •Age 18 years and older
- •Adequate hematologic, renal and hepatic function, defined by:
- •Absolute neutrophil count (ANC) ≥ 1.5 x109/L
- •Platelet count ≥ 100 x 109/L,
- •Hemoglobin ≥ 60 g/L
- •International normalized ratio (INR) < 1.5 x upper limit of normal (ULN)
- •Activated partial thromboplastin time (APTT) < 1.5 x ULN
- •Plasma creatinine < 1.5 x ULN
- •Total bilirubin < 2.5 x ULN (in the presence of Gilbert's syndrome or indirect hyperbilirubinemia caused by hemolysis)
- •Aspartate transaminase (AST) < 2.5 x ULN
- •Alanine transaminase (ALT) < 2.5 x ULN
- •Ability of the prospective subject to understand and willingness to sign written informed consent document
排除标准
- •Patients who have received any other investigational agent within 4 weeks before enrollment.
- •Patients who have had a VOE/ACS in the previous 4 weeks before enrollment.
- •Stroke or transient ischemic attack within 6 months before enrollment.
- •Myocardial infarction within 6 months before enrollment, unstable angina, New York Heart Association class II or greater congestive heart failure, or uncontrolled hypertension (systolic BP > 160 mmHg and/or diastolic BP > 100 mmHg).
- •Congenital long QT syndrome, or corrected QT interval ( QTc) > 450 milliseconds (msec) in males and > 470 mSec in females on EKG.
- •Uncontrolled arrhythmia or any history of clinically significant arrhythmia in the past 6 months
- •Clinically-significant chronic obstructive pulmonary disease or asthma that is not controlled by medication.
- •A history of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer or other solid tumors curatively treated with no evidence of disease for ≥ 2 years.
- •Current anticoagulant or antiplatelet therapy, except for prophylactic doses of low molecular weight heparins or low-dose aspirin.
- •History of allergic reactions attributed to compounds of similar chemical composition to NVX-
- •Women who are pregnant or breastfeeding.
- •Inability to comply with study procedures.
- •History or evidence of any other clinically-significant condition that, in the opinion of the investigator, would pose a risk to subject safety or interfere with study procedures, evaluation or completion.
- •Patients with active VOE or ACS or other significant current acute complication of SCD.
研究组 & 干预措施
NVX-508
Administration of 1, 2 or 4 doses of NVX-508 at three dose levels; 0.05ml/kg. 0.1ml/kg and 0.17ml/kg in a 3 + 3 design.
干预措施: NVX-508 (Drug)
结局指标
主要结局
Maximum tolerated dose of NVX-508
时间窗: 1 year
次要结局
未报告次要终点
研究者
Amma Owusu-Ansah, MD
Assistant Professor of Medicine and Clinical Director, Center for Translational and International Hematology
University of Pittsburgh