Fostamatinib for Hospitalized Adults With COVID-19

Coronavirus Disease 2019 (COVID-19) is the disease caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). SARS-CoV-2 primarily infects the upper and lower respiratory tract and can lead to acute respiratory distress syndrome (ARDS) in a subset of patients with a known high mortality rate. Additionally, some patients develop other organ dysfunction including myocardial injury, acute kidney injury, shock along with endothelial dysfunction and subsequently micro and macrovascular thrombosis.

Much of the underlying pathology of SARS-CoV-2 is thought to be secondary to a dysregulated immune response and more recently a hypercoagulable state leading to immunothrombosis. Currently, two therapies have shown efficacy in large multicenter trials for the treatment of COVID-19, one of which is an antiviral (remdesivir) and the other is an immunosuppressant corticosteroid meant to dampen the immune response (dexamethasone).

Spleen tyrosine kinase (SYK) is a cytoplasmic tyrosine kinase involved in the intracellular signaling pathways of many different immune cells. In this pilot study we propose to use fostamatinib (an SYK inhibitor) as a targeted therapy for the immunological complications of hospitalized patients with COVID-19. The biological mechanisms by which SYK inhibition may improve outcomes in patients with COVID-19 include the inhibition of pro-inflammatory cytokines by monocytes and macrophages, decreased production of neutrophil extracellular traps (NETs) by neutrophils, and inhibition of platelet aggregation; three pathways that are mediated through Fc receptors (FcR) recognition of antigen-antibody complexes or activation of c-type lectin receptors (CLEC).

This is a randomized, double-blind, placebo-controlled trial of fostamatinib for the treatment of hospitalized patients with COVID-19.

We will randomly assign fostamatinib or matched placebo (1:1) to 60 eligible COVID-19 patients who are a 5 to 7 on the 8-point scale (requiring supplemental oxygen via nasal canula or noninvasive ventilation, requiring mechanical ventilation or extracorporeal membrane oxygenation).

• INCLUSION CRITERIA:

• Patient must be hospitalized, or had their inpatient stay extended, for COVID-19.
• Age >=18 years
• Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
• Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
• Females of childbearing potential must agree to be abstinent or use a medical acceptable form of contraception from the time of enrollment through 30 days after last day of study drug
• Laboratory confirmed SARS-CoV-2 RT-PCR test within 7 days of enrollment
• Illness of any duration with SpO2 of less than 94% on room air requiring supplemental oxygen via nasal canula or non-invasive mechanical ventilation, or mechanical ventilation or ECMO (5 to 7 on the 8-point scale)

Exclusion criteria

• ALT or AST > 5 times the upper limit of normal (ULN) or ALT or AST >= 3 x ULN and total bilirubin > 2 x ULN.
• Estimated glomerular filtration rate (eGFR) <30ml/min
• Pregnancy or breast feeding
• Anticipated discharge in the next 72 hours
• Allergy to study medication
• Uncontrolled hypertension (systolic blood pressure >160mmHg or diastolic blood pressure >100mmHg)
• Shock or hypotension at the time of enrollment
• Neutrophil count <1000/microliter
• Concern for bacterial or fungal sepsis
• Received immunomodulatory treatment within 30 days prior to enrollment e.g., Bruton's tyrosine kinase/phosphoinositide 3 kinase/Janus kinase inhibitor or cytokine-targeting biologic therapy (anti-TNF, IL-6)
• Received a live vaccine the last 4 weeks
• Those who were cognitively impaired or mentally disabled prior to COVID diagnosis
• Participation in another clinical trial for the treatment of COVID-19.