EFFICACY and SAFETY OF BEVACIZUMAB (ZIRABEV®) IN PATIENTS WITH SEVERE HYPOXEMIC COVID-19

Corona Virus Infection Clinical Trial

— BEVA  

Official title:

TRIAL EVALUATING EFFICACY and SAFETY OF BEVACIZUMAB (ZIRABEV®) IN PATIENTS WITH SEVERE HYPOXEMIC COVID-19, NESTED IN THE CORIMUNO-19 COHORT

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04822818
• Other study ID #: APHP200375-BEVA
• Status: Completed
• Phase: Phase 3
• Start date: April 17, 2021
• Est. completion date: July 11, 2022

Study information

• Verified date: December 2022
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the most frequent complications of the COVID-19 pandemic. In these conditions, hypoxemia may result from : i) a pulmonary vascular dilatation resulting from an impaired hypoxic pulmonary vasoconstriction and leading to ventilation-perfusion mismatching within the lungs and ii) thrombosis-mediated perfusion defects. Pulmonary vascular dilation might be due to a relative failure of the physiological acute hypoxic pulmonary vasoconstriction, in the context of an over-activation of a regional vasodilatation cascade, as part of a dysfunctional inflammatory process. Perfusion abnormalities associated with pulmonary vascular dilation are suggestive of intrapulmonary shunting toward areas where gas exchange is impaired, ultimately leading to a worsening ventilation-perfusion mismatch, a regional hypoxia and a profound hypoxemia.

Increased plasma levels of VEGF have been reported in moderate to severe COVID-19 pneumonia, highlighting the role of VEGF in the pathophysiology of the disease. A better prognosis has been reported in critically ill patients with lower levels of growth factors, HGF and VEGF-A at the time of ICU admission. Recent data of the study NCT 04275414 by Pang J et al have suggested that patients receiving a single-dose of bevacizumab have improved their oxygen support status in 92% of cases during a 28-day follow-up period, as compared with 62% of cases in an external cohort receiving standard care.

Correcting endothelial permeability and vasodilatation with VEGF-targeted therapy could allow repair damaged vascular endothelium, have an indirect anti-inflammatory effect (limiting alveolar exudation of circulating inflammatory and procoagulant mediators) and improve oxygenation and therefore reduce the proportion of patients with severe forms requiring ICU referral and finally patient death. This clinical trial will therefore focus on the specific efficacy of bevacizumab in COVID-19 patients with severe hypoxemia.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 96
• Est. completion date: July 11, 2022
• Est. primary completion date: April 10, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients included in the CORIMUNO-19 cohort

• Patients hospitalized in conventional ward or in the ICU belonging to the following groups: OMS Progression scale 6, 7, 8 AND no acute pulmonary embolism on CT-scan performed in the preceding 72 hours no pulmonary evident bacterial coinfection or superinfection evaluated by non-invasive procedures (serology, antigens, nasopharynx PCR, sputum examination, blood cultures…)

Exclusion Criteria:

• Patients in OMS progression class 9

• Patients with exclusion criteria to the CORIMUNO-19 cohort

• Pregnancy

• Active cancer with ongoing treatment

• acute use of NIV for COPD exacerbation or cardiac decompensation associated to COVID-19

• Oxygen patient requiring long-term oxygen before hospitalization

• Patient already included in an interventional research

• Risk of bleeding especially hemoptysis, active venous or arterial thromboembolic disease and recent surgery during the last 3 weeks

• Hypersensitivity to the active substance (bevacizumab) or to any of the excipients (sucrose, succinic acid, disodium edetate, polysorbate 80, sodium hydroxide, water for injection

• Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies

• Persistant uncontrolled arterial hypertension after using to anti-hypertensive drugs

• Current documented bacterial infection not controlled by antibiotics.

• Active viral diseases (especially active herpes, chickenpox, shingles),

• Active tuberculosis or disseminated strongyloidiasis

• patient with known active hepatitis or with increased level of SGOT or SGPT =5N

• Patient with anormal laboratory results: Absolute neutrophil count (ANC) = 1.0 x 109/L, Platelets (PLT) < 50 G /L

Related Conditions & MeSH terms

• Communicable Diseases
• Corona Virus Infection
• Coronaviridae Infections
• Coronavirus Infections
• COVID-19
• Infections
• Nidovirales Infections
• Respiratory Tract Diseases
• Respiratory Tract Infections
• RNA Virus Infections
• SARS (Severe Acute Respiratory Syndrome)
• Severe Acute Respiratory Syndrome
• Virus Diseases

Intervention

Drug:
• BEVA+SOC
Bevacizumab : 7.5 mg / kg (with a maximum of 750 mg) on day 1 (D1) SOC : patients will receive the best of standard of care including corticosteroids, anticoagulant, antibiotics and tociluzimab
• SOC
patients will receive the best of standard of care including corticosteroids, anticoagulant, antibiotics and tociluzimab

Locations

Country	Name	City	State
France	Hôpital TENON	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The time to recovery for a category 0 to 5 on the WHO Progression scale	Defined as the first day on which the patient meets the criteria for category 0 to 5 on the OMS Progression scale	28 days after randomization
Secondary	Clinical status on the OMS Progression scale	WHO progression scale: Uninfected; non viral RNA detected: 0 Asymptomatic; viral RNA detected: 1 Symptomatic; Independent: 2 Symptomatic; Assistance needed: 3 Hospitalized; No oxygen therapy: 4 Hospitalized; oxygen by mask or nasal prongs: 5 Hospitalized; oxygen by NIV or High flow: 6 Intubation and Mechanical ventilation, pO2/FIO2>=150 OR SpO2/FIO2>=200: 7 Mechanical ventilation, (pO2/FIO2<150 OR SpO2/FIO2<200) OR vasopressors (norepinephrine >0.3 microg/kg/min): 8 Mechanical ventilation, pO2/FIO2<150 AND vasopressors (norepinephrine >0.3 microg/kg/min), OR Dialysis OR ECMO: 9 Dead: 10	at 7, 14, and 28 days after randomization
Secondary	Overall survival	Time to death after randomization	at 7, 14, and 28 days after randomization
Secondary	Ventilator free days		at 7, 14, and 28 days after randomization
Secondary	High flow free days		at 7, 14, and 28 days after randomization
Secondary	Time to oxygen supply weaning		at 7, 14, and 28 days after randomization
Secondary	Changes in VEGF plasma levels		at 7, and 14 days after randomization
Secondary	Comparison of the incidence of Grade 3 or 4 events will be will be described in each group with their 95% CI	Description : defined according to CTCAE v5.0 will be will be described in each group with their 95% CI	Day 28
Secondary	Proportion of Adverse Event	will be described in each group with their 95% CI	Day 28, day 120 after randomization