Fostamatinib for Hospitalized Adults With COVID-19

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

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

Study Overview

• Status: Completed
• Conditions: Coronavirus Disease 2019
• Intervention / Treatment: Drug: fostamatinib; Drug: Placebo

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Health Systems

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

  1. Patient must be hospitalized, or had their inpatient stay extended, for COVID-19.
  2. Age >=18 years
  3. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
  4. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
  5. 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
  6. Laboratory confirmed SARS-CoV-2 RT-PCR test within 7 days of enrollment
  7. 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:

1. ALT or AST > 5 times the upper limit of normal (ULN) or ALT or AST >= 3 x ULN and total bilirubin > 2 x ULN.
2. Estimated glomerular filtration rate (eGFR) <30ml/min
3. Pregnancy or breast feeding
4. Anticipated discharge in the next 72 hours
5. Allergy to study medication
6. Uncontrolled hypertension (systolic blood pressure >160mmHg or diastolic blood pressure >100mmHg)
7. Shock or hypotension at the time of enrollment
8. Neutrophil count <1000/microliter
9. Concern for bacterial or fungal sepsis
10. 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)
11. Received a live vaccine the last 4 weeks
12. Those who were cognitively impaired or mentally disabled prior to COVID diagnosis
13. Participation in another clinical trial for the treatment of COVID-19.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention; fostamatinib in combination with standard of care (SOC) for the treatment of COVID-19	Drug: fostamatinib; 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.
Placebo Comparator: Intervention - Placebo; Placebo in combination with standard of care (SOC) for the treatment of COVID-19	Drug: Placebo; Placebo tablets to match fostamatinib 100 mg and 150 mg will be provided.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Jeffrey R Strich, M.D., National Institutes of Health Clinical Center (CC)

Publications and helpful links

General Publications

• Strich JR, Tian X, Samour M, King CS, Shlobin O, Reger R, Cohen J, Ahmad K, Brown AW, Khangoora V, Aryal S, Migdady Y, Kyte JJ, Joo J, Hays R, Collins AC, Battle E, Valdez J, Rivero J, Kim IH, Erb-Alvarez J, Shalhoub R, Chakraborty M, Wong S, Colton B, Ramos-Benitez MJ, Warner S, Chertow DS, Olivier KN, Aue G, Davey RT, Suffredini AF, Childs RW, Nathan SD. Fostamatinib for the Treatment of Hospitalized Adults With Coronavirus Disease 2019: A Randomized Trial. Clin Infect Dis. 2022 Aug 24;75(1):e491-e498. doi: 10.1093/cid/ciab732.
• Strich JR, Ramos-Benitez MJ, Randazzo D, Stein SR, Babyak A, Davey RT, Suffredini AF, Childs RW, Chertow DS. Fostamatinib Inhibits Neutrophils Extracellular Traps Induced by COVID-19 Patient Plasma: A Potential Therapeutic. J Infect Dis. 2021 Mar 29;223(6):981-984. doi: 10.1093/infdis/jiaa789.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2020
• Primary Completion (Actual): March 30, 2021
• Study Completion (Actual): April 30, 2021

Study Registration Dates

• First Submitted: October 6, 2020
• First Submitted That Met QC Criteria: October 6, 2020
• First Posted (Actual): October 8, 2020

Study Record Updates

• Last Update Posted (Actual): March 2, 2022
• Last Update Submitted That Met QC Criteria: February 28, 2022
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: SARS-CoV-2; ARDS; Cytokines; Spleen Tyrosine Kinase
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 10000110; 000110-H

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No