Coronaviridae Infections, Corona Virus Infection, Nidovirales Infections, Respiratory Tract Diseases, Respiratory Tract Infections, RNA Virus Infections, SARS (Severe Acute Respiratory Syndrome), Virus Diseases
Conditions
Keywords
COVID-19 pneumonia, severe hypoxemia, VEGF, bevacizumab
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.
Interventions
DRUGBEVA+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
DRUGSOC
patients will receive the best of standard of care including corticosteroids, anticoagulant, antibiotics and tociluzimab
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 |
| 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 |
| Time to oxygen supply weaning | at 7, 14, and 28 days after randomization | — |
Countries
France
Outcome results
None listed