The Efficacy and Safety of Bevacizumab in Patients With Severe Covid-19: a Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 588
- 试验地点
- 1
- 主要终点
- The time from randomization to clinical improvement
研究概览
简要总结
The novel coronavirus (SARS-CoV-2) is a new strain of coronavirus found in human in 2019, which causes epidemic worldwide. Novel coronavirus disease (COVID-19) causes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in patients with severe COVID-19. Pulmonary edema is the key detrimental feature of ALI/ARDS. Autopsy of patients died from COVID-19 reported that, pulmonary mucus exudation was more severe and obvious than SARS infection. Pulmonary CT scanning and pathological findings also suggest that pulmonary edema caused by inflammatory exudation is a distinguished feature of COVID-19. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is known as the most potent factor to increase vascular permeability, with the induction effect 50,000 times stronger than histamine. Bevacizumab is an anti-VEGF recombinant humanized monoclonal antibody, which has been used in anti-tumor treatment since 2004, with considerable reliability and clinical safety. This trial will provide high level evidence to answer whether bevacizumab is efficacy and safe medication for patients with severe COVID-19.
详细描述
Evident increase of VEGF levels in serum has been displayed on novel pneumonia patients. The investigators also conducted a pilot study of 93 patients with severe COVID-19 that confirmed the significantly elevated level of plasma and serum VEGF.
At the beginning of 2020, the investigators proposed the concept of using anti-VEGF treatment for patients with severe COVID-19 and conducted a pilot study (NCT04275414). Among the 27 enrolled participants treated with bevacizumab, it was found that the clinical recovery status, PaO2/FiO2, and pulmonary exudation on imaging were significantly improved than the external controls in the same center during the same period. This provides good preliminary basis for this RCT.
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)
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 old, both genders;
- •Confirmed COVID-19 diagnosis (any body fluid tested positive for SARS-CoV-2 nucleic acid by PCR, or positive for SARS-CoV-2 antigen);
- •Respiratory rate ≥ 30 times/min, partial pressure of oxygen (PaO2)/ fraction of inspiration O2 (FiO2)≤ 300mmHg (1mmHg = 0.133kPa), or SpO2 ≤ 93% at rest without supplemental oxygen;
- •Article (3) above is newly appeared within 7 days;
- •Chest radiography or computed tomography shows bilateral chest infiltrates.
排除标准
- •Unable to obtain informed consent.
- •Physician with more than 5 years of clinical experience determines that death was inevitable within 24 hours.
- •Severe hepatic dysfunction (Child Pugh score ≥ C, or AST> 5 times the upper limit); Severe renal dysfunction (estimated glomerular filtration rate ≤ 30mL/ min/1.73 m2) or receive continuous renal replacement therapy, hemodialysis, or peritoneal dialysis.
- •Uncontrolled hypertension (sitting systolic blood pressure> 160mmHg, or diastolic blood pressure>100mmHg); previous history of hypertension crisis or hypertensive encephalopathy.
- •Poorly controlled heart diseases, such as NYHA class II and above cardiac insufficiency, unstable angina pectoris, myocardial infarction within 1 year before enrollment, supraventricular or ventricular arrhythmia need treatment or intervention.
- •Severe or above chronic obstructive pulmonary disease (GOLD grade, FEV1/FVC < 0.5).
- •Hereditary bleeding tendency or coagulopathy;
- •Arterial/venous thromboembolic events within 6 months before enrollment, such as ischemic stroke, transient ischemic attack, deep venous thrombosis, pulmonary embolism, etc. Severe vascular disease (including aneurysms or arterial thrombosis requiring surgery) within 6 months before enrollment.
- •Unhealed wounds, active gastric ulcers or fractures. Gastrointestinal perforation, gastrointestinal fistula, abdominal abscess, visceral fistula formation within 6 months before enrollment. Major surgery (including preoperative Chest biopsy) or major trauma (such as a fracture) within 28 days before enrollment. May have surgery during the trial.
- •Severe, active bleeding such as hemoptysis, gastrointestinal bleeding, central nervous system bleeding, and nosebleeds within 1 month before enrollment.
- •Malignant tumors within 5 years before enrollment.
- •Allergic to bevacizumab or its components.
- •Active tuberculosis, uncontrollable infection, untreated active hepatitis or HIV-positive patients.
- •Pregnant and lactating women and those planning to get pregnant.
- •Participated in other clinical trials, not considered suitable for this study by the researchers.
研究组 & 干预措施
Bevacizumab
Bevacizumab 7.5mg/kg body weight, intravenous drip, single-dose administration, and standard of care, including prophylactic doses of low molecular weight heparin or unfractionated heparin without contraindications, and therapeutic doses of anticoagulants with the evidence of thrombosis risk or occurrence.
干预措施: Bevacizumab (Drug)
Bevacizumab
Bevacizumab 7.5mg/kg body weight, intravenous drip, single-dose administration, and standard of care, including prophylactic doses of low molecular weight heparin or unfractionated heparin without contraindications, and therapeutic doses of anticoagulants with the evidence of thrombosis risk or occurrence.
干预措施: Standard care (Other)
Placebo
Placebo (inactive excipient) 7.5mg/kg body weight, intravenous drip, single-dose administration, and standard of care, including prophylactic doses of low molecular weight heparin or unfractionated heparin without contraindications, and therapeutic doses of anticoagulants with the evidence of thrombosis risk or occurrence.
干预措施: Placebo (Other)
Placebo
Placebo (inactive excipient) 7.5mg/kg body weight, intravenous drip, single-dose administration, and standard of care, including prophylactic doses of low molecular weight heparin or unfractionated heparin without contraindications, and therapeutic doses of anticoagulants with the evidence of thrombosis risk or occurrence.
干预措施: Standard care (Other)
结局指标
主要结局
The time from randomization to clinical improvement
时间窗: 28 days
The time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever comes first.
次要结局
- Improvement of lymphocyte count(day 7 and day 14 after randomization, or before discharge)
- SAE, AE(From date of randomization until the date of discharge, up to 28 days)
- Duration of mechanical ventilation (days)(From date of randomization until the date of discharge, up to 28 days)
- Time to reach level 1 on the seven-category ordinal scale(up to 60 days)
- Improvement of CRP(day 7 and day 14 after randomization, or before discharge)
- Improvement of LDH(day 7 and day 14 after randomization, or before discharge)
- Duration of non-invasive ventilator or nasal high flow oxygen inhalation(From date of randomization until the date of discharge, up to 28 days)
- All-cause mortality(From date of randomization until the date of discharge, up to 60 days)
- Improvement of pulmonary lesions(day 7 and day 14 after randomization, or before discharge)
- Intubation rate(From date of randomization until the date of discharge, up to 28 days)
- PaO2/FiO2 level(day 1, day 3, day 7 and day 14 after randomization, or before discharge)