A Randomised, Double-blind, Placebo-controlled Study to Investigate the Safety and Efficacy of Intravenous Imatinib Mesylate (Impentri®) in Subjects With Acute Respiratory Distress Syndrome Induced by COVID-19
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 67
- 试验地点
- 2
- 主要终点
- Change in extravascular lung water index
研究概览
简要总结
The SARS-CoV2 pandemic and resulting COVID-19 infection has led to a large increase in the number of patients with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterised by inflammation and fluid in the lungs. There is no proven therapy to reduce fluid leak, also known as pulmonary oedema, in ARDS. However, recent studies have discovered that imatinib strengthens the cell barrier and prevents fluid leak in the lungs in inflammatory conditions, while leaving the immune response intact. The investigators hypothesize that imatinib limits pulmonary oedema observed in ARDS due to COVID-19, and may thus help to reverse hypoxemic respiratory failure and to hasten recovery.
The hypothesis will be tested by conducting a randomised, double-blind, parallel-group, placebo-controlled multi-centre clinical study of intravenous imatinib in 90 mechanically-ventilated, adult subjects with COVID-19-related ARDS.
Study participants will receive the study drug (imatinib or placebo) twice daily for a period of 7 days. The effect of the intervention will be tested by measuring extravascular lung water (i.e. pulmonary oedema) difference between day 1 and day 4, using a PiCCO catheter (= pulse contour cardiac monitoring device).
Other measurements will include regular blood tests to investigate the safety and the pharmacokinetic properties of imatinib, as well as biomarkers of inflammation and cellular dysfunction. Furthermore, parameters of ventilation and morbidity and mortality will be recorded as secondary outcome measures.
详细描述
- INTRODUCTION
1.1 Background of ARDS due to COVID-19
The COVID-19 pandemic has led to an unanticipated increase of the number of patients with ARDS admitted to the ICU, contributing to high morbidity and mortality, as well as an unprecedented consumption of medical resources. COVID-19 is caused by a coronavirus (scientific name: SARS-CoV-2), a non-segmented, positive sense RNA virus. Although most SARS-CoV-2 infections have an asymptomatic or mild course of disease (80%), COVID-19 has a detrimental course in a minority of patients (20%), particularly in older patients or patients with pulmonary or cardiovascular comorbidities. In these cases, COVID-19 infection is characterized by damage to the alveolocapillary wall and extensive pulmonary capillary leak. The alveolar flooding results in impairment of oxygen diffusion and severe hypoxemic respiratory failure. In Chinese registries these cases of COVID-19 disease were classified as either 'severe' in case of low oxygen saturation or 'critical' when invasive mechanical ventilation was needed or multi-organ failure occurred. Radiological imaging demonstrates extensive ground glass opacities, consistent with alveolar oedema.
Radiological as well as pathological examination demonstrated that critical COVID-19 infections closely mimic Acute Respiratory Distress Syndrome (ARDS), a condition characterized by damage to the alveolo-capillary membrane by various insults. Mortality in ICU treated 'critical' COVID-19 patients is comparable to mortality in ARDS patients. Of the patients admitted with COVID-19 infection to hospital, 17-35% develop ARDS, requiring ICU admission or even invasive mechanical ventilation (29-91%). According to recent reviews, mortality may mount up to 15-20% (hospitalized patients) to even 40% in ICU patients. For these reasons, the current COVID-19 pandemic has resulted in a huge increase in the incidence of ARDS with a homogenous aetiology i.e., SARS-CoV2 infection.
According to the Berlin definition, ARDS is '...an acute diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue...[with] hypoxemia and bilateral radiographic opacities, associated with increased venous admixture, increased physiological dead space and decreased lung compliance'. It is characterised by an acute onset, with bilateral infiltrates on chest imaging due to pulmonary oedema, and with severe hypoxemia despite mechanical ventilation. Pathophysiologically, ARDS results from an overwhelming inflammatory process involving alveolar epithelial and vascular endothelial injury in the lung which can be infective and non-infective in origin. The early phase of ARDS is characterized by alveolar flooding with protein-rich fluid due to increased vascular permeability. Pulmonary oedema then leads to the clinical manifestation of poor lung compliance, severe hypoxaemia, and bilateral infiltrates on chest radiograph. It also leads to alveolar epithelial injury of type I cells, which contributes further to the pulmonary oedema. Despite decades of efforts, there is currently no registered drug to target pulmonary vascular permeability in ARDS.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blinded trial in which the study participant and legal representative, as well as the treating nurses, physicians and researchers are blinded from viewing randomisation allocation.
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
- •Age ≥ 18 years;
- •Moderate-severe ARDS, as defined by Berlin definition for ARDS (onset within 1 week of a known clinical insult or new or worsening respiratory symptoms, bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules, respiratory failure not fully explained by cardiac failure or fluid overload and P/F ratio ≤200 mmHg with PEEP ≥5 cmH2O), and intubated for mechanical ventilation.
- •PCR positive for SARS-CoV2 within the current disease episode.
- •Provision of signed written informed consent from the patient or patient's legally authorised representative;
排除标准
- •Persistent septic shock (>24h) with a Mean Arterial Pressure (MAP) ≤ 65 mm Hg and serum lactate level > 4 mmol/L (36 mg/dL) despite adequate volume resuscitation and vasopressor use (norepinephrine > 0.2 μg/kg/min) for > 6 hours;
- •Pre-existing chronic pulmonary disease, including:
- •Known diagnosis of Interstitial Lung disease
- •Known diagnosis of COPD GOLD Stage IV or FEV1<30% predicted
- •DLCO <45% (if test results are available)
- •Total lung capacity (TLC) < 60% of predicted (if test results are available);
- •Chronic home oxygen treatment;
- •Pre-existing heart failure with a known left ventricular ejection fraction <40%;
- •Active treatment of haematological or non-haematological cancer with targeted immuno- or chemotherapy, or thoracic radiotherapy in the last year;
- •Currently receiving extracorporeal life support (ECLS);
- •Severe chronic liver disease with Child-Pugh score > 12;
- •Subjects in whom a decision to withdraw medical care is made (e.g. palliative setting);
- •Inability of the ICU staff to initiate IMP administration within 48 hours of intubation;
- •Known to be pregnant or breast-feeding;
- •Enrolled in a concomitant clinical trial of an investigational medicinal product;
- •White blood count < 2.5x109/l;
- •Haemoglobin < 4.0 mmol/l;
- •Thrombocytes < 50x109/l;
- •The use of strong CYP3A4 inducers, including the following drugs:
- •Carbamazepine, efavirenz, enzalutamide, fenobarbital, fenytoine, hypericum, mitotaan, nevirapine, primidon, rifabutine, rifampicine;
研究组 & 干预措施
Intravenous imatinib mesylate (Impentri®)
Patients receiving the active investigational medicinal product will be receiving imatinib 200mg b.i.d. (administered as an 8 mg/mL solution for i.v. infusion) for 7 days.
干预措施: Imatinib Mesylate intravenous solution (Drug)
Placebo solution
Patients receiving the placebo comparator will be receiving the same amount of intravenous solution, however containing 0.01M acetate buffer with 1.9% glycerol.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in extravascular lung water index
时间窗: Measurements conducted on days 1 - 7. Change measured between Day 1 and Day 4
Change in extravascular lung water index (EVLWi) between day 1 and day 4, measured by PiCCO catheter.
次要结局
- Driving pressure as an indicator of global lung strain(Recorded on days 1, 2, 4, 7, 10 and, if available, day 28.)
- Mechanical power as quantification of the energy load delivered to the lung per positive pressure breath(Recorded on days 1, 2, 4, 7, 10 and, if available, day 28.)
- Matrix metalloproteinases as markers of inflammation(All markers measured on days 1, 2, 4, 7 and 10.)
- Surfactant as biomarker of lung epithelial injury(All markers measured on days 1, 2, 4, 7 and 10.)
- Angiopoietin-1 and -2 as biomarkers of endothelial activation and injury(All markers measured on days 1, 2, 4, 7 and 10.)
- Compliance as a measure of respiratory mechanics(Recorded on days 1, 2, 4, 7, 10 and, if available, day 28.)
- Imatinib metabolite AGP(Measurements on day 1 at moment of infusion (i.e. T0) and 2, 4 and 8 hours after start of IMP infusion. Further measurements once daily on days 2, 4 and 7.)
- NT-proBNP as drug safety parameter(All drug safety parameters are measured and recorded on days 1, 2, 4, 7 and 10.)
- Pulmonary vascular permeability(PVPi measured and recorded on days 1 - 7.)
- D-dimer as an inflammatory biomarker(All markers measured on days 1, 2, 4, 7 and 10.)
- Hemoglobin cell count as drug safety parameter(All drug safety parameters are measured and recorded on days 1, 2, 4, 7 and 10.)
- Blood cell count as drug safety parameter(All drug safety parameters are measured and recorded on days 1, 2, 4, 7 and 10.)
- Serum creatinine as measure of kidney function(All drug safety parameters are measured and recorded on days 1, 2, 4, 7 and 10.)
- Estimated glomerular filtration rate as measure of kidney function(All drug safety parameters are measured and recorded on days 1, 2, 4, 7 and 10.)
- PaO2/FiO2 ratio as measure of gas-exchange(Recorded on days 1, 2, 4, 7, 10 and, if available, day 28.)
- Oxygenation index as measure of gas-exchange(Recorded on days 1, 2, 4, 7, 10 and, if available, day 28.)
- Pro-inflammatory cytokines(All markers measured on days 1, 2, 4, 7 and 10.)
- Soluble thrombomodulin as a biomarker of endothelial activation and injury(All markers measured on days 1, 2, 4, 7 and 10.)
- Protein biomarkers of lung epithelial injury(All markers measured on days 1, 2, 4, 7 and 10.)
- SOFA score as organ function and outcome measure(The SOFA score will be recorded on days 1, 2, 4, 7, 10 and, if available, day 28.)
- Serum bilirubin as drug safety parameter(All drug safety parameters are measured and recorded on days 1, 2, 4, 7 and 10.)
- Corrected QT interval on ECG(The corrected QT interval on ECG will be recorded on days 1 - 10.)
- Thoracic ultrasound(Measurements on day 1 and day 4.)
- WHO ordinal scale for clinical improvement as functional outcome measure(The WHO ordinal scale will be recorded on days 1, 2, 4, 7, 10 and, if available, day 28.)
- Morbidity and mortality outcomes(All measures are recorded as days until day 28.)
- 28-day mortality(28-day mortality will be recorded in percentage of patients deceased until day 28.)
- Electrolytes as drug safety parameters(All drug safety parameters are measured and recorded on days 1, 2, 4, 7 and 10.)
- Liver enzymes as drug safety parameter(All drug safety parameters are measured and recorded on days 1, 2, 4, 7 and 10.)
- Reporting of adverse and serious adverse events(Adverse and serious adverse events will be recorded daily until day 28.)
- Total concentration as a pharmacokinetic measure of imatinib(Measurements on day 1 at moment of infusion (i.e. T0) and 2, 4 and 8 hours after start of IMP infusion. Further measurements once daily on days 2, 4 and 7.)
- Free fraction as a pharmacokinetic measure of imatinib(Measurements on day 1 at moment of infusion (i.e. T0) and 2, 4 and 8 hours after start of IMP infusion. Further measurements once daily on days 2, 4 and 7.)
- Imatinib metabolite albumin(Measurements on day 1 at moment of infusion (i.e. T0) and 2, 4 and 8 hours after start of IMP infusion. Further measurements once daily on days 2, 4 and 7.)
研究者
Dr. Jurjan Aman
Dr. J. Aman, Trial Coordinator
Amsterdam UMC, location VUmc