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.

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.

We will share the study protocol, SAP, ICF, CSR and analytic code on the day of article publication.

On the day of article publication.

By inquiring of principal investigator or central contact person.