Fostamatinib for Hospitalized Adults With COVID-19

Study Overview
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Brief Summary
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Background: COVID-19 is a new disease caused by SARS-CoV-2 that was identified in 2019. Some people who get sick with COVID-19 become ill requiring hospitalization. There are some medicines that may help with recovery. Researchers want to see if a drug called fostamatinib may help people who are hospitalized with COVID-19. Objective: To learn if fostamatinib is safe in patients who are hospitalized with COVID-19 and gain earlier insight into whether it improves outcomes. Eligibility: Adults age 18 and older who are hospitalized with COVID-19. Design: Participants will be screened with a physical exam, including vital signs and weight. They will have a blood test and chest x-ray. They will have a COVID-19 test as a swab of either the back of the throat or the back of the nose. They will take a pregnancy test if needed. Participants will be randomly assigned, to take either fostamatinib pills or a placebo twice daily for up to 14 days in addition to standard of care for COVID-19. If they can swallow, they will take the pills by mouth with water. If they cannot swallow or are on mechanical ventilation, the pills will be crushed, mixed with water, and given through a tube placed through the nostril, or placed in the mouth, down the esophagus, and into the stomach. Blood samples will be taken daily. Participants will return to the Clinical Center for safety follow-up visits. At these visits, they will have a physical exam and blood tests. If they cannot visit the Clinical Center, they will be contacted by phone or have a telehealth visit. Participation will last for about two months

Detailed Description
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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).

Official Title
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A Phase II Study Evaluating Fostamatinib for Hospitalized Adults With COVID-19

Conditions
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Coronavirus Disease 2019

Intervention / Treatment
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* Drug: Placebo
* Drug: fostamatinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention<br>fostamatinib in combination with standard of care (SOC) for the treatment of COVID-19 | Drug: fostamatinib<br>* The study intervention is fostamatinib, an inhibitor of spleen tyrosine kinase that will be administered orally at a dose of 150 mg twice daily for 14 days or 28 doses. Subjects will receive standard of care and be randomized to receive fostamatinib or matching placebo.<br>|
| Placebo Comparator: Intervention - Placebo<br>Placebo in combination with standard of care (SOC) for the treatment of COVID-19 | Drug: Placebo<br>* Placebo tablets to match fostamatinib 100 mg and 150 mg will be provided.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least 1 Serious Adverse Event | Number of participants with at least 1 serious adverse event by day 29 using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CTCAE is a list of common adverse event (AE) terms. Each AE term is defined and accompanied by a grading scale (1 to 5) that indicates the severity of the AE. Grading ranges from Grade 1 which is mild to Grade 5 which is death. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Sustained Recoveries Defined by Ordinal Scale Score of 3 or Less | Time to sustained recovery determined by ordinal scale score of 3 or less and defined as time to recovery [either discharge from the hospital or hospitalization for infection control reasons only], with the recovery status sustained through day 29. The ordinal scale is an assessment of the clinical status. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | day 29 | 
| Number of Participants Who Progress to Mechanical Ventilation | Number of participants who progress to mechanical ventilation by day 29 | day 29 | 
| Number of Participants With Cumulative Clinical Endpoint of Death | Number of Participants with Cumulative Clinical Endpoint of Death at Day 14, Day 28 and Day 60 | day 14, day 28, day 60 | 
| Number of Grade 3 and 4 Adverse Events Through Day 60 | Number of Grade 3 and 4 AE through day 60 using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CTCAE is a list of common adverse event (AE) terms. Each AE term is defined and accompanied by a grading scale (1 to 5) that indicates the severity of the AE. Grading ranges from Grade 1 which is mild to Grade 5 which is death. | Day 60 | 
| Participant Score on Ordinal Scale | Participant score on ordinal scale at day 15 and day 29. The ordinal scale is an assessment of the clinical status. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | Day 15, Day 29 | 
| Change in C-Reactive Protein Levels From Baseline | Change in C-Reactive Protein (CRP) blood levels from baseline. The upper limit of normal is 5 mg/L (milligrams per liter). | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 
| Change in Fibrinogen Levels From Baseline. | Change in Fibrinogen blood levels from baseline. The upper limit of normal is Fibrinogen 466 milligrams per decilitre (mg/dL). | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 
| Change in D-Dimer Levels From Baseline | Change in D-Dimer blood levels from baseline. The upper limit of normal is 0.50 mcg/mL (microgram per milliliter). | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 
| Change in Ferritin Levels From Baseline | Change in Ferritin levels from baseline. The upper limit of normal for Ferritin is 400 mcg/L (micrograms per liter). | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 
| Change in Interleukin 6 (IL6) Levels From Baseline | Change in Interleukin 6 (IL6) blood levels from baseline. The upper limit of normal for IL6 is 1.8 picograms per milliliter (pg/mL). | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 
| Median Days Participants Were Admitted to Intensive Care Unit | Median days participants were admitted to Intensive Care Unit (ICU) by day 29 | Day 29 | 
| Relative Change in SpO2/FiO2 Ratio | Relative change in PaO2/FiO2 or SpO2/FiO2 ratio. | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 
| Change in SOFA Score From Baseline | Change in SOFA score from baseline (day 1). The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems. The score is calculated on admission and every 24 hours until discharge using the worst parameters measured during the prior 24 hours. Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure). The worst measurement was defined as the measure that correlated to the highest number of points. The SOFA score ranges from 0 to 24. | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 
| Median Days on Participants Received Supplemental Oxygen | Median days on participants received supplemental oxygen through day 29 | day 29 | 
| The Number of Participants That Experienced Acute Renal Failure | The number of participants that experienced acute renal failure by day 29. Acute renal failure defined as increase in serum creatinine by ≥0.3mg/dL within 48 hours or increase in serum creatinine by ≥1.5 times baseline which is known or presumed to have occurred within the prior seven days. | day 29 | 
| Number of Participants That Experienced a Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) | Number of participants that experienced a deep vein thrombosis (DVT) or pulmonary embolism (PE) by day 29 | day 29 | 
| Change in Absolute Lymphocyte Count Levels From Baseline | Change in Absolute lymphocyte count blood levels from baseline. | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 
| Change in Absolute Neutrophil Count Levels From Baseline | Change in Absolute neutrophil count blood levels from baseline. | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 
| Change in Platelet Count Levels From Baseline | Change in Platelet count blood levels from baseline. | Day 3, Day 5, Day 8, Day 11, Day 15, Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, Cytokines, Spleen Tyrosine Kinase, ARDS