Use of Defibrotide to Reduce Progression of Acute Respiratory Failure Rate in Patients With COVID-19 Pneumonia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- to able to reduce the progression of acute respiratory failure
研究概览
简要总结
Phase II, prospective, interventional, single-arm, multicentric, open label trial, with a parallel retrospective collection of data on not treated patients from IRCCS, San Raffaele Scientific Institute included in the institutional observational study.
A sample of 50 patients with COVID-19 pneumonia will allow to detect an absolute reduction in the rate of Respiratory-failure at day+14 after treatment of 20%, assuming that the actual rate of failure in the corresponding not treated patients is 70% (alpha=5%, power=90%, two-sided test). The software PASS15 was used for calculations.
The study will also include a parallel retrospective group of temporally concomitant patients from IRCCS, San Raffaele Scientific Institute, who did not receive an experimental treatment and who are enrolled in an already IRB approved observational study
详细描述
As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. The 2019 novel Coronavirus (2019-nCoV; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) has spread rapidly since its recent identification in patients with severe pneumonia in Wuhan, China. The clinical spectrum of COVID-19 varies from asymptomatic or pauci-symptomatic forms to clinical conditions characterized by respiratory failure that necessitates mechanical ventilation and support in an intensive care unit (ICU), to multiorgan and systemic manifestations in terms of sepsis, septic shock, and multiple organ dysfunction syndromes (MODS). Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality.
The cytokine profile of COVID-19 patients supports that the fatality is driven by a virally-triggered, self-propagating, hyper-inflammatory state (Mehta et al, 2020). Elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p<0·001) and IL-6 (p<0·0001) have been found to be independent predictors of fatality in COVID-19 patients in China (Ruan et al, 2020).
VOD, known as Veno-Occlusive-Disease or Synusoidal Obstruction Syndrome, is the most characterized of a spectrum of post bone marrow transplantation (BMT) syndromes (including ELS, IPS or aGVHD) characterized by reactive endothelial activation and damage, endothelial-driven paracrine signaling and a pro-inflammatory and pro-coagulant state. Severe VOD frequently progresses to Multi Organ Failure and is characterized by high mortality (>80%), characterized mostly by lung and kidney failure.
High levels (elevated early in the course of the disease) of IL-6, IL-8 and TNF-alpha characterize VOD and the other post-BMT endothelial diseases (Schots et al, 2003, Gugliotta et al 1994, Remberger et al 1997, Symington et al, 1992). In detail, IL-8 may be involved in the respiratory failure following ARDS, a frequent and fatal outcome of sVOD patients. Intriguingly, high ferritin levels are a well recognized risk factor for the development of VOD in both adult and pediatric settings.
Furthermore, the histopathological examination of lung lesions in VOD syndromes show early alveolar epithelial and lung endothelial injury, resulting in accumulation of protein- and fibrin-rich inflammatory edematous fluid in the alveolar space and progression to interstitial fibrosis, at later stages.
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
盲法说明
Italian Hospital
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented COVID-19 pneumonia: defined as upper respiratory tract specimen (nasopharyngeal swab (NPS) or viral throat swab) positive for COVID-19 and/or imaging at computed tomography scan suggestive of COVID-19 pneumonia
- •Oxygen saturation (SaO2) of 92% or less without oxygen support, or reduction of 3% from basal value of SaO2, or a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2) (PaO2/FiO2) below
- •Any gender
- •Age >= 18 years
- •Written informed consent or as per Ethical Committee indication in case of patients not able to express written informed consent
排除标准
- •Onset of COVID-19 pneumonia >14 days
- •Orotracheal intubation
- •Uncontrolled systemic infection (other than COVID-19)
- •Concomitant use of thrombolytic therapy Concomitant systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin inhibitors and direct factor Xa inhibitors)
- •Haemodynamic instability, defined as inability to maintain mean arterial pressure with single pressor support
- •Hypersensitivity to the active substance or to any of the excipients of the experimental drug
- •Patients who, based on the investigator's clinical judgement, are not able to receive the treatment
- •Pregnancy or breastfeeding patient
研究组 & 干预措施
Arm Label
with the experimental drug: Defibrotide 25 mg/kg body weight total dose in 2 hours duration infusion each, every 6 hours (Defibrotide 6.25 mg/kg body weight each dose) Treatment duration = 7 days
干预措施: Defibrotide Injection (Drug)
结局指标
主要结局
to able to reduce the progression of acute respiratory failure
时间窗: 14 days
To demonstrate that the treatment with Defibrotide administered intravenously in addition to the best available therapy according to institutional guidelines (protease inhibitors antiviral treatment and hydroxychloroquine (HCQ), and if needed, metilprednisolone is able to reduce the progression of acute respiratory failure, the need of mechanical ventilation, the transfer to the intensive care unit or death, in patients with severe COVID-19 pneumonia. Patients with a baseline PaO2/FiO2 \>= 200: progression of respiratory failure is defined by: 1. severe gas transfer deficit (PaO2/FiO2 \< 200); 2. persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use of accessory respiratory muscles, paradoxical respiratory movements); 3. transfer to the intensive care unit; 4. death. The rate will be calculated as the proportion of patients who experienced at least one of the events above by day+14 from treatment start.
次要结局
- Adverse events(7 days)
- duration of hospitalization(14 days)
- systemic inflammation(14 days)
- overall survival(28 days)
研究者
Ciceri Fabio
Prof., Director Clinical Trial Unit
IRCCS San Raffaele