Bevacizumab in Patients With Severe Covid-19 (BEST)

The Efficacy and Safety of Bevacizumab in Patients With Severe Covid-19: a Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: COVID-19 Pneumonia
• Intervention / Treatment: Drug: Bevacizumab; Other: Placebo; Other: Standard care

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.

• Study Type: Interventional
• Enrollment (Estimated): 588
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jiaojiao Pang, Dr; Phone Number: 18560089129; Email: jiaojiaopang@126.com

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250012
      • Recruiting
      • Qilu Hospital of Shandong University
      • Contact: Jiaojiao Pang, Dr; Phone Number: +86 18560089129; Email: jiaojiaopang@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	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 Names: Recombinant anti-VEGF humanized monoclonal antibody injection; 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.
Placebo Comparator: 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.	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 Names: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The time from randomization to clinical improvement	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.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	All-cause mortality	From date of randomization until the date of discharge, up to 60 days
Time to reach level 1 on the seven-category ordinal scale	Days from randomization to the clinical status of reaching level 1 on the seven--category ordinal scale	up to 60 days
PaO2/FiO2 level	The ratio of partial pressure of oxygen to fraction of inspiration O2	day 1, day 3, day 7 and day 14 after randomization, or before discharge
Improvement of pulmonary lesions	The change of volumes of pulmonary exudation shown on CT compared to baseline	day 7 and day 14 after randomization, or before discharge
Improvement of lymphocyte count	The change of the level of lymphocyte count compared to baseline	day 7 and day 14 after randomization, or before discharge
Improvement of CRP	The change of the level of C-reactive protein compared to baseline	day 7 and day 14 after randomization, or before discharge
Improvement of LDH	The change of the level of lactate dehydrogenase compared to baseline	day 7 and day 14 after randomization, or before discharge
Intubation rate	Intubation rate	From date of randomization until the date of discharge, up to 28 days
Duration of mechanical ventilation (days)	Days of mechanical ventilation	From date of randomization until the date of discharge, up to 28 days
Duration of non-invasive ventilator or nasal high flow oxygen inhalation	Days of non-invasive ventilator or nasal high flow oxygen inhalation	From date of randomization until the date of discharge, up to 28 days
SAE, AE	Serious adverse event, adverse event	From date of randomization until the date of discharge, up to 28 days

Collaborators and Investigators

• Sponsor: Qilu Hospital of Shandong University
• Collaborators: Shandong Provincial Hospital; Qingdao Municipal Hospital; China-Japan Friendship Hospital; Renmin Hospital of Wuhan University; Second Affiliated Hospital of Xi'an Jiaotong University; First Affiliated Hospital of Wenzhou Medical University; Jining Medical University; Yantai Yuhuangding Hospital; Zibo Central Hospital; Anqing Municipal Hospital; Shandong Jining No.1 People's Hospital; Linyi People's Hospital; Weihai Municipal Hospital; Weifang People's Hospital; Weifang Medical University; Qilu Hospital of Shandong University (Qingdao); Rizhao People's Hospital; Zibo Municipal Hospital; Zhejing Provincial People's Hospital; The First Affiliated Hospital of Wannan Medical College; The Fourth Affiliated Hospital Zhejing University School of Medicine; Weifang Second People's Hospital; Weifang Hospital of Traditional Chinese Medicine
• Investigators: Principal Investigator: Yihai Cao, Dr, Qilu Hospital of Shandong University, Karolinska Institutet; Principal Investigator: Yuguo Chen, Dr, Qilu Hospital of Shandong University

Publications and helpful links

General Publications

• 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. Erratum In: Lancet. 2020 Jan 30;:
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2023
• Primary Completion (Estimated): November 30, 2023
• Study Completion (Estimated): December 31, 2023

Study Registration Dates

• First Submitted: March 9, 2020
• First Submitted That Met QC Criteria: March 9, 2020
• First Posted (Actual): March 12, 2020

Study Record Updates

• Last Update Posted (Actual): June 27, 2023
• Last Update Submitted That Met QC Criteria: June 26, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: QLEmer

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share the study protocol, SAP, ICF, CSR and analytic code on the day of article publication.
• IPD Sharing Time Frame: On the day of article publication.
• IPD Sharing Access Criteria: By inquiring of principal investigator or central contact person.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No