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

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Recruiting

CT.gov ID

NCT04822818

Collaborator

(none)

174

Enrollment

Location

Arms

13.5

Anticipated Duration (Months)

12.9

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Corona Virus Infection SARS (Severe Acute Respiratory Syndrome) Virus Diseases Coronaviridae Infections Nidovirales Infections RNA Virus Infections Respiratory Tract Infections Respiratory Tract Diseases	Drug: BEVA+SOC Drug: SOC	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

174 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Apr 17, 2021

Anticipated Primary Completion Date :

Jun 1, 2022

Anticipated Study Completion Date :

Jun 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bevacizumab + 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	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
Active Comparator: SOC SOC : patients will receive the best of standard of care including corticosteroids, anticoagulant, antibiotics and tociluzimab	Drug: SOC patients will receive the best of standard of care including corticosteroids, anticoagulant, antibiotics and tociluzimab

Arm

Intervention/Treatment

Experimental: Bevacizumab + 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

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

Active Comparator: SOC

SOC : patients will receive the best of standard of care including corticosteroids, anticoagulant, antibiotics and tociluzimab

Drug: SOC

patients will receive the best of standard of care including corticosteroids, anticoagulant, antibiotics and tociluzimab

Outcome Measures

Primary Outcome Measures

The time to recovery for a category 0 to 5 on the WHO Progression scale [28 days after randomization]
Defined as the first day on which the patient meets the criteria for category 0 to 5 on the OMS Progression scale

Secondary Outcome Measures

Clinical status on the OMS Progression scale [at 7, 14, and 28 days after randomization]
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
Overall survival [at 7, 14, and 28 days after randomization]
Time to death after randomization
Ventilator free days [at 7, 14, and 28 days after randomization]
High flow free days [at 7, 14, and 28 days after randomization]
Time to oxygen supply weaning [at 7, 14, and 28 days after randomization]
Changes in VEGF plasma levels [at 7, and 14 days after randomization]
Comparison of the incidence of Grade 3 or 4 events will be will be described in each group with their 95% CI [Day 28]
Description : defined according to CTCAE v5.0 will be will be described in each group with their 95% CI
Proportion of Adverse Event [Day 28, day 120 after randomization]
will be described in each group with their 95% CI

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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