Pilot Study of Single Dose Bevacizumab as Treatment for Acute Respiratory Distress Syndrome (ARDS) in COVID-19 Patients

Study Overview
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Brief Summary
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Our hypothesis is that treating ARDS caused by COVID-19 with bevacizumab improves mortality. This is a phase II, multi-centered, randomized, open label, two-armed clinical trial to study the safety and efficacy of bevacizumab in COVID-19 positive patients who consequently developed ARDS (acute respiratory distress syndrome) and who have previously received anti-viral and anti-inflammatory treatment.

Detailed Description
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The vascular endothelial growth factor (VEGF) improves vascular capillarity, which plays an important role in the uncontrolled inflammatory reaction that happens in ARDS. As opposed to this event, angiogenic therapy (like bevacizumab) is known to contribute to normal vascularization, relevant for regaining vascular permeability. Studies in animal models have shown that treating ARDS with anti-VEGF therapy is effective.

Official Title
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Pilot Study of Single Dose Bevacizumab as Treatment for Acute Respiratory Distress Syndrome (ARDS) in COVID-19 Patients

Conditions
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ARDS, Human, Coronavirus Infection

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: BAT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age equal or over 18 and under 90 years old. Confirmed COVID-19 positive diagnostic through PCR. Radiological image compatible with non-cardiogenic bilateral pleuropulmonary exudate. Patient has received anti-viral and anti-inflammatory therapy. Present any of the following clinical-functional criteria: Respiratory distress: Tachypnea> 30 breaths / minute Partial arterial oxygen pressure (PaO2) / Fraction of inspiration (FiO2) ≤ 300 mmHg Signed informed consent, directly or delegated. Exclusion Criteria: Severe liver dysfunction (Child Pugh ≥ 3 or AST> 5 times normal) Severe renal dysfunction with glomerular filtration <30 mL / minute or under treatment with hemodialysis or peritoneal dialysis. Poorly controlled hypertension (BPs> 160 mmHg or TAd <100 mmHg) or having a history previous hypertensive crisis or hypertensive encephalopathy. History of poorly controlled heart disease with a NYHA> 2. History of thrombosis in the previous 6 months. Signs of active bleeding. Open wounds, gastrointestinal perforation. Diagnosis of thrombophilic diseases or hemorrhagic diathesis. Active viral hepatitis or HIV not properly treated. Intolerance or allergy to bevacizumab or its components. Pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase II, multi-centered, randomized, open label, two-armed clinical trial to study the safety and efficacy of bevacizumab in COVID-19 positive patients who consequently developed ARDS (acute respiratory distress syndrome) and who have previously received anti-viral and anti-inflammatory treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BEVACIZUMAB<br>Patients will receive best available treatment (BAT) for COVID-19 plus single dose bevacizumab calculated as 7,5 mg/kg diluted in 250cc of saline solution during 90 minutes. | Drug: Bevacizumab<br>* Patients will receive best available treatment (BAT) for COVID-19 plus a single dose of bevacizumab calculated as 7,5 mg/kg diluted in 250cc of saline solution during 90 minutes.<br>|
| Active Comparator: BEST AVAILABLE TREATMENT<br>Patients will receive best available treatment for COVID-19. | Drug: BAT<br>* Patients will receive best available treatment for COVID-19.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Mortality | After 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PaO2/FiO2 | Ratio calculation | 6 hours before bevacizumab administration and 24 hours,72 hours,7 days,14 days and 28 days after. | 
| Clinical improvement according to scale recommended by WHO for COVID19 | Clinical improvement according to WHO scale (World Health Organization) for COVID19 which goes from 1 to 7 points. | 24 hours, 72 hours, 7 days, 14 days and 28 days after treatment. | 
| Time to clinical improvement as stated in the National Early Warning Score 2 (NEWS) | NEWS assesses clinical risk on a scale of 1 (low) to 8 (high) | From randomization until improvement of 2 points in the scale or until hospital discharge, whatever happens first, assessed up to 28 days. | 
| Time to improvement of oxygenation | Improvement shown during, at least, 48 hours. | From randomization until outcome event assessed up to 28 days. | 
| Time to improvement of Sp2/O2 ratio regarding the worst Sp2/O2 ratio obtained before bevacizumab treatment. | Time to improvement of Sp2/O2 ratio regarding the worst Sp2/O2 ratio obtained before bevacizumab treatment | From randomization until first documented Sp2/O2 ratio improvement, assessed up to 28 days. | 
| Time to absence of oxygen need to maintain a saturation equal or over 93% | Time to absence of oxygen need to maintain a saturation equal or over 93% | From randomization until patient doesn't need oxygen to mantain 93% saturation, assessed up to 28 days. | 
| Favorable radiological evaluation. | Dictated by 3 radiologists. | From randomization until first documented radiology improvement, assessed up to 28 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS, SARS-CoV-2, Bevacizumab