Clinical trial NCT04305106: Bevacizumab in Patients With Severe Covid-19
Official title: The Efficacy and Safety of Bevacizumab in Patients With Severe Covid-19: a Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: COVID-19 Pneumonia
Lead sponsor: Qilu Hospital of Shandong University
Sponsor class: OTHER
Collaborators: name: China-Japan Friendship Hospital
name: Renmin Hospital of Wuhan University
name: Second Affiliated Hospital of Xi'an Jiaotong University
name: Zhejing Provincial People's Hospital
name: First Affiliated Hospital of Wenzhou Medical University
name: Anqing Municipal Hospital
name: First Affiliated Hospital of Wannan Medical College
name: The Fourth Affiliated Hospital Zhejing University School of Medicine
name: Shandong Provincial Hospital
name: Linyi People's Hospital
name: Jining Medical University
name: Jining First People's Hospital
name: Weifang Second People's Hospital
name: Weifang Medical University
name: Yantai Yuhuangding Hospital
name: Weihai Municipal Hospital
name: Rizhao People's Hospital
name: Qingdao Municipal Hospital
name: Qilu Hospital of Shandong University (Qingdao)
name: Weifang People's Hospital
name: Weifang Hospital of Traditional Chinese Medicine
name: Zibo Central Hospital
First posted: 2020-03-12
Enrollment: 588
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: The time from randomization to clinical improvement
timeFrame: 28 days
Secondary outcomes:
measure: Intubation rate
timeFrame: From date of randomization until the date of discharge, up to 28 days
measure: Duration of mechanical ventilation (days)
timeFrame: From date of randomization until the date of discharge, up to 28 days
measure: Duration of non-invasive ventilator or nasal high flow oxygen inhalation
timeFrame: From date of randomization until the date of discharge, up to 28 days
measure: All-cause mortality
timeFrame: From date of randomization until the date of discharge, up to 60 days
measure: Time to reach level 1 on the seven-category ordinal scale
timeFrame: up to 60 days
measure: PaO2/FiO2 level
timeFrame: day 1, day 3, day 7 and day 14 after randomization, or before discharge
measure: Improvement of pulmonary lesions
timeFrame: day 7 and day 14 after randomization, or before discharge
measure: Improvement of lymphocyte count
timeFrame: day 7 and day 14 after randomization, or before discharge
measure: Improvement of CRP
timeFrame: day 7 and day 14 after randomization, or before discharge
measure: Improvement of LDH
timeFrame: day 7 and day 14 after randomization, or before discharge
measure: SAE, AE
timeFrame: From date of randomization until the date of discharge, up to 28 days
Other outcomes:
Locations:
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shandong
Study officials:
affiliation: Qilu Hospital of Shandong University, Karolinska Institutet
name: Yihai Cao, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Qilu Hospital of Shandong University
name: Yuguo Chen, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.
citation: Pang J, Xu F, Aondio G, Li Y, Fumagalli A, Lu M, Valmadre G, Wei J, Bian Y, Canesi M, Damiani G, Zhang Y, Yu D, Chen J, Ji X, Sui W, Wang B, Wu S, Kovacs A, Revera M, Wang H, Jing X, Zhang Y, Chen Y, Cao Y. Efficacy and tolerability of bevacizumab in patients with severe Covid-19. Nat Commun. 2021 Feb 5;12(1):814. doi: 10.1038/s41467-021-21085-8.