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.
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.
Drug: Bevacizumab
Bevacizumab (7.5mg/kg BW) + Saline (100ml) Bevacizumab will be administered in a single dose with no less than 90 minutes of intravenous infusion under ECG monitoring.
Other Name: Recombinant anti-VEGF humanized monoclonal antibody injection
Other: Placebo
Placebo (7.5mg/kg BW) + Saline (100ml) The placebo drug will be administered in a single dose with no less than 90 minutes of intravenous infusion under ECG monitoring.
Other Name: Inactive excipient
Other: Standard care
Standard 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.
Inclusion Criteria:
1. Age: ≥18 years old, both genders;
2. Confirmed COVID-19 diagnosis (any body fluid tested positive for SARS-CoV-2 nucleic
acid by PCR, or positive for SARS-CoV-2 antigen);
3. 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;
4. Article (3) above is newly appeared within 7 days;
5. Chest radiography or computed tomography shows bilateral chest infiltrates.
Exclusion Criteria:
1. Unable to obtain informed consent.
2. Physician with more than 5 years of clinical experience determines that death was
inevitable within 24 hours.
3. 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.
4. Uncontrolled hypertension (sitting systolic blood pressure> 160mmHg, or diastolic
blood pressure>100mmHg); previous history of hypertension crisis or hypertensive
encephalopathy.
5. 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.
6. Severe or above chronic obstructive pulmonary disease (GOLD grade, FEV1/FVC < 0.5).
7. Hereditary bleeding tendency or coagulopathy;
8. 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.
9. 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.
10. Severe, active bleeding such as hemoptysis, gastrointestinal bleeding, central nervous
system bleeding, and nosebleeds within 1 month before enrollment.
11. Malignant tumors within 5 years before enrollment.
12. Allergic to bevacizumab or its components.
13. Active tuberculosis, uncontrollable infection, untreated active hepatitis or
HIV-positive patients.
14. Pregnant and lactating women and those planning to get pregnant.
15. Participated in other clinical trials, not considered suitable for this study by the
researchers.
Qilu Hospital of Shandong University
Jinan, Shandong, China
Investigator: Jiaojiao Pang, Dr
Contact: +86 18560089129
jiaojiaopang@126.com
Jiaojiao Pang, Dr
18560089129
jiaojiaopang@126.com