Bevacizumab in Severe or Critical Patients With COVID-19 Pneumonia (BEST-CP)

• ClinicalTrials.gov Identifier: NCT04275414
• Recruitment Status: Completed
• First Posted: February 19, 2020
• Last Update Posted: September 14, 2020
• Sponsor: Qilu Hospital of Shandong University
• Collaborators: Renmin Hospital of Wuhan University; Moriggia-Pelascini Gravedona Hospital
• Information provided by (Responsible Party): Qilu Hospital of Shandong University

Study Description

Brief Summary:

The novel identified coronavirus (SARS-CoV-2) in 2019 causes an nationwide outbreak as well as public health crisis in China, and expands globally. Pulmonary edema is one of the most detrimental symptoms and usually presents in severe and critical coronavirus disease (COVID-19), resulting in dyspnea, acute lung injury (ALI) ,acute respiratory distress syndrome (ARDS), and even death. Recent evidence revealed higher levels of blood Vascular Endothelial Growth Factor (VEGF) in COVID-19 patients compared with healthy controls. VEGF is considered as the most potent vascular permeability inducers. Numerous studies have revealed that VEGF was a key factor and a potential therapeutic target in ALI and ARDS. Bevacizumab, an anti-VEGF drug, approved by the FDA on February 26, 2004 and widely used in clinical oncotherapy, is a promising drug for ALI/ARDS in COVID-19 through suppression of pulmonary edema.

Condition or disease	Intervention/treatment	Phase
Coronavirus Infections	Drug: Bevacizumab Injection	Phase 2

Detailed Description:

In December 2019, a new identified coronavirus (SARS-CoV-2) outbreak in Wuhan, causes public health crisis in China and spreads worldwide. On February 11,2020, the World Health Organization officially named the disease caused by the new coronavirus "COVID-19". The Chinese Government takes stronger and harsher measures to control the progression of its outbreak. Meanwhile, five editions of "Diagnosis and Treatment for Novel Coronavirus-Infected Pneumonia" has been timely and continuously issued, which play extremely important roles in guiding the clinical management of COVID-19 nationwide in China.

The symptoms of human infection with SARS-CoV-2 are generally fever, fatigue, dry cough and dyspnea. Noteworthy, a considerable percentage of COVID-19 cases have rapidly progressed to severe and critical type, among which acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the most common complications, resulting in a large number of pneumonia hospitalized patients requiring supplemental oxygen, mechanical ventilation, or even ECMO.Pulmonary edema is a detrimental feature as well as a key causal factor of ALI/ARDS.

Vascular Endothelial Growth Factor (VEGF) is considered as the most potent vascular permeability inducers. Recent evidence has revealed higher VEGF levels in COVID-19 patients compared with healthy controls. The rise of VEGF levels may be caused by hypoxia, severe inflammation, and upregulation of the infected respiratory tract epithelium itself. Numerous studies have confirmed a key role of VEGF as potential therapeutic target in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) due do increase vascular permeability and induce pulmonary edema.

Thus, Bevacizumab, an anti-VEGF medication, may offer a unique approach to treat ALI/ARDS caused by COVID-19. Bevacizumab is a humanized monoclonal antibody with long half-life. It has been approved by the FDA on February 26, 2004 and widely used in clinical oncotherapy, with the pharmacokinetics and pharmacodynamics having been widely understood. Therefore, Bevacizumab is a promising drug for the treatment of ALI/ARDS as well as reduction of mortality in severe and critical COVID-19 patients through suppression of pulmonary edema.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effecacy and Safety of Bevacizumab in Severe Patients With Covid-19: a Pilot Study (BEST-CP)
• Actual Study Start Date: February 15, 2020
• Actual Primary Completion Date: April 5, 2020
• Actual Study Completion Date: May 2, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: bevacizumab plus standard care; Under ECG monitoring, give bevacizumab 500mg + 0.9% sodium chloride solution 100ml via intravenous drip, time is no less than 90min.	Drug: Bevacizumab Injection; Bevacizumab 500mg + normal saline (NS) 100ml, ivdrip ≥90min

Outcome Measures

Primary Outcome Measures :

1. Partial arterial oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) ratio [ Time Frame: 24 hours ]
   Partial arterial oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) ratio
2. Partial arterial oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) ratio [ Time Frame: 7 days ]
   Partial arterial oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) ratio

Secondary Outcome Measures :

1. Rate of improvement of oxygen-support status [ Time Frame: 28 days ]
   The oxygen-support status includes 6 levels: mechanical ventilation, non-invasive ventilation, a transition status of alternate use of non-invasive ventilation and high-flow oxygen, high-flow oxygen, low-flow oxygen and ambient air. The improvement of oxygen-support status is defined as switch from a higher level of oxygen-support to a lower level.
2. The change of areas of pulmonary lesions shown on chest radiological imaging (chest CT or X-ray) [ Time Frame: 7 days ]
   The areas of pulmonary lesions are analysised by a professional imaging software.
3. Blood lymphocyte counts [ Time Frame: 7 days ]
   Blood lymphocyte counts
4. Level of CRP [ Time Frame: 7 days ]
   Level of CRP
5. Level of hs-CRP [ Time Frame: 7 days ]
   Level of hs-CRP
6. All-cause mortality [ Time Frame: 28 days ]
   All-cause mortality
7. Discharge rate [ Time Frame: 28 days ]
   Discharge rate

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Age 18 to 80.
2. Confirmed COVID-19 diagnosis(including the clinically confirmed cases in Hubei).
3. Accord with any of the following: respiratory distress, RR ≥ 30 breaths/min; or SpO2 ≤ 93% at rest; or partial arterial oxygen pressure (PaO2) / fraction of inspiration O2 (FiO2) >100mmHg and ≤ 300mmHg (1mmHg = 0.133kPa).
4. Chest imaging confirms lung involvement and has inflammatory exudation or pleural effusion.

Exclusion Criteria:

1. Cannot obtain informed consent.
2. 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.
3. Unsatisfactory controlled hypertension (seated systolic blood pressure> 160mmHg, or diastolic blood pressure> 100mmHg); previous history of hypertension crisis or hypertensive encephalopathy.
4. 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.
5. Hereditary bleeding tendency or coagulopathy; received full-dose anticoagulant or thrombolytic therapy within10 days before enrollment, or have taken non-steroidal anti-inflammatory drugs with platelet suppression within 10 days before enrollment (Except those who use small doses of aspirin ≤325mg / day for preventive use).
6. 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.
7. 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.
8. Severe, active bleeding such as hemoptysis, gastrointestinal bleeding, central nervous system bleeding, and nosebleeds within 1 month before enrollment.
9. Malignant tumors within 5 years before enrollment.
10. Allergic to bevacizumab or its components.
11. Untreated active hepatitis or HIV-positive patients.
12. Pregnant and lactating women and those planning to get pregnant.
13. Participated in other clinical trials, not considered suitable for this study by the researchers.

Contacts and Locations

Locations

China, Hubei

Renmin Hospital of Wuhan University

Wuhan, Hubei, China

China, Shandong

Qilu Hospital of Shandong University

Jinan, Shandong, China, 250012

Italy

Moriggia-Pelascini Gravedona Hospital

Gravedona, Italy

Sponsors and Collaborators

Qilu Hospital of Shandong University

Renmin Hospital of Wuhan University

Moriggia-Pelascini Gravedona Hospital

Investigators

• Principal Investigator: Yuguo Chen, Dr; Qilu Hospital of Shandong University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Qilu Hospital of Shandong University
• ClinicalTrials.gov Identifier: NCT04275414
• Other Study ID Numbers: QLEmer20200214
• First Posted: February 19, 2020
• Last Update Posted: September 14, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Qilu Hospital of Shandong University:

COVID-19; Bevacizumab; pneumonia

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Bevacizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors