Back to results

Bevacizumab in Patients With Severe Covid-19 (BEST)

Primary Purpose

COVID-19 Pneumonia

Status

Recruiting

Phase

Phase 3

Locations

China

Study Type

Interventional

Intervention

Bevacizumab

Placebo

Standard care

About this trial

This is an interventional treatment trial for COVID-19 Pneumonia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age: 18-80 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; and PaO2/FiO2>100mmHg;
Article (3) above is newly appeared within 5 days;
Chest radiography or computed tomography shows bilateral chest infiltrates.

Exclusion Criteria:

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;
Thrombosis within 6 months before enrollment. And from those patients, screen who had arterial / venous thromboembolic events, such as, ischemic stroke, transient ischemic attack, deep venous thrombosis, pulmonary embolism, etc. within 1 year ahead of enrollment. 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, bacterial, fungal, or viral infection other than SARS-CoV-2, 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.

Sites / Locations

Qilu Hospital of Shandong UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Bevacizumab

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Intubation rate

Duration of mechanical ventilation (days)

Days of mechanical ventilation

Duration of non-invasive ventilator or nasal high flow oxygen inhalation

Days of non-invasive ventilator or nasal high flow oxygen inhalation

All-cause mortality

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

PaO2/FiO2 level

The ratio of partial pressure of oxygen to fraction of inspiration O2

Improvement of pulmonary lesions

The change of volumes of pulmonary exudation shown on CT compared to baseline

Improvement of lymphocyte count

The change of the level of lymphocyte count compared to baseline

Improvement of CRP

The change of the level of C-reactive protein compared to baseline

Improvement of LDH

The change of the level of lactate dehydrogenase compared to baseline

SAE, AE

Serious adverse event, adverse event

Full Information

NCT ID

NCT04305106

First Posted

March 9, 2020

Last Updated

June 26, 2023

Sponsor

Qilu Hospital of Shandong University

Collaborators

China-Japan Friendship Hospital, Renmin Hospital of Wuhan University, Second Affiliated Hospital of Xi'an Jiaotong University, Zhejing Provincial People's Hospital, First Affiliated Hospital of Wenzhou Medical University, Anqing Municipal Hospital, The First Affiliated Hospital of Wannan Medical College, The Fourth Affiliated Hospital Zhejing University School of Medicine, Shandong Provincial Hospital, Linyi People's Hospital, Jining Medical University, Shandong Jining No.1 People's Hospital, Weifang Second People's Hospital, Weifang Medical University, Yantai Yuhuangding Hospital, Weihai Municipal Hospital, Rizhao People's Hospital, Qingdao Municipal Hospital, Qilu Hospital of Shandong University (Qingdao), Weifang People's Hospital, Weifang Hospital of Traditional Chinese Medicine, Zibo Central Hospital, Zibo municipal hospital

1. Study Identification

Unique Protocol Identification Number

NCT04305106

Brief Title

Bevacizumab in Patients With Severe Covid-19

Acronym

BEST

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

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Recruiting

Study Start Date

January 12, 2023 (Actual)

Primary Completion Date

November 30, 2023 (Anticipated)

Study Completion Date

December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Qilu Hospital of Shandong University

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

COVID-19 Pneumonia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

588 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Bevacizumab

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Bevacizumab

Other Intervention Name(s)

Recombinant anti-VEGF humanized monoclonal antibody injection

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Placebo

Other Intervention Name(s)

Inactive excipient

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Standard care

Intervention Description

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.

Primary Outcome Measure Information:

Title

The time from randomization to clinical improvement

Description

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.

Time Frame

28 days

Secondary Outcome Measure Information:

Title

Intubation rate

Description

Intubation rate

Time Frame

From date of randomization until the date of discharge, up to 28 days

Title

Duration of mechanical ventilation (days)

Description

Days of mechanical ventilation

Time Frame

From date of randomization until the date of discharge, up to 28 days

Title

Duration of non-invasive ventilator or nasal high flow oxygen inhalation

Description

Days of non-invasive ventilator or nasal high flow oxygen inhalation

Time Frame

From date of randomization until the date of discharge, up to 28 days

Title

All-cause mortality

Description

All-cause mortality

Time Frame

From date of randomization until the date of discharge, up to 60 days

Title

Time to reach level 1 on the seven-category ordinal scale

Description

Days from randomization to the clinical status of reaching level 1 on the seven--category ordinal scale

Time Frame

up to 60 days

Title

PaO2/FiO2 level

Description

The ratio of partial pressure of oxygen to fraction of inspiration O2

Time Frame

day 1, day 3, day 7 and day 14 after randomization, or before discharge

Title

Improvement of pulmonary lesions

Description

The change of volumes of pulmonary exudation shown on CT compared to baseline

Time Frame

day 7 and day 14 after randomization, or before discharge

Title

Improvement of lymphocyte count

Description

The change of the level of lymphocyte count compared to baseline

Time Frame

day 7 and day 14 after randomization, or before discharge

Title

Improvement of CRP

Description

The change of the level of C-reactive protein compared to baseline

Time Frame

day 7 and day 14 after randomization, or before discharge

Title

Improvement of LDH

Description

The change of the level of lactate dehydrogenase compared to baseline

Time Frame

day 7 and day 14 after randomization, or before discharge

Title

SAE, AE

Description

Serious adverse event, adverse event

Time Frame

From date of randomization until the date of discharge, up to 28 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jiaojiao Pang, Dr

Phone

18560089129

jiaojiaopang@126.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yihai Cao, Dr

Organizational Affiliation

Qilu Hospital of Shandong University, Karolinska Institutet

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Yuguo Chen, Dr

Organizational Affiliation

Qilu Hospital of Shandong University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Qilu Hospital of Shandong University

City

Jinan

State/Province

Shandong

ZIP/Postal Code

250012

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jiaojiao Pang, Dr

Phone

+86 18560089129

jiaojiaopang@126.com

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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.

Citations:

PubMed Identifier

31986264

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. Erratum In: Lancet. 2020 Jan 30;:

Results Reference

background

PubMed Identifier

33547300

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.

Results Reference

background

Learn more about this trial

Bevacizumab in Patients With Severe Covid-19

We'll reach out to this number within 24 hrs