Clinical trial NCT04579393: Fostamatinib for Hospitalized Adults With COVID-19
Official title: A Phase II Study Evaluating Fostamatinib for Hospitalized Adults With COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Coronavirus Disease 2019
Keywords: SARS-CoV-2
Cytokines
Spleen Tyrosine Kinase
ARDS
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2020-10-08
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: * 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.

Primary outcomes:
measure: Number of Participants With at Least 1 Serious Adverse Event
timeFrame: Day 29
Secondary outcomes:
measure: Number of Participants With Sustained Recoveries Defined by Ordinal Scale Score of 3 or Less
timeFrame: day 29
measure: Number of Participants Who Progress to Mechanical Ventilation
timeFrame: day 29
measure: Number of Participants With Cumulative Clinical Endpoint of Death
timeFrame: day 14, day 28, day 60
measure: Number of Grade 3 and 4 Adverse Events Through Day 60
timeFrame: Day 60
measure: Participant Score on Ordinal Scale
timeFrame: Day 15, Day 29
measure: Change in C-Reactive Protein Levels From Baseline
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
measure: Change in Fibrinogen Levels From Baseline.
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
measure: Change in D-Dimer Levels From Baseline
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
measure: Change in Ferritin Levels From Baseline
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
measure: Change in Interleukin 6 (IL6) Levels From Baseline
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
measure: Median Days Participants Were Admitted to Intensive Care Unit
timeFrame: Day 29
measure: Relative Change in SpO2/FiO2 Ratio
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
measure: Change in SOFA Score From Baseline
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
measure: Median Days on Participants Received Supplemental Oxygen
timeFrame: day 29
measure: The Number of Participants That Experienced Acute Renal Failure
timeFrame: day 29
measure: Number of Participants That Experienced a Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE)
timeFrame: day 29
measure: Change in Absolute Lymphocyte Count Levels From Baseline
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
measure: Change in Absolute Neutrophil Count Levels From Baseline
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
measure: Change in Platelet Count Levels From Baseline
timeFrame: Day 3, Day 5, Day 8, Day 11, Day 15, Day 29
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
city: Falls Church
country: United States
facility: INOVA Health Systems
state: Virginia
Study officials:
affiliation: National Institutes of Health Clinical Center (CC)
name: Jeffrey R Strich, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.