International Sites: Novel Experimental COVID-19 Therapies Affecting Host Response

Study Overview
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Brief Summary
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The overarching goal of the Master Protocol is to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19.

Detailed Description
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has resulted in a global pandemic. The clinical spectrum of COVID-19 infection is broad, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and death. Between 13 and 40% of patients become hospitalized, up to 30% of those hospitalized require admission for intensive care, and there is a 13% inpatient mortality rate. The reasons for hospitalization include respiratory support, as well as support for failure of other organs, including the heart and kidneys. The risk of thrombotic complications is increased, even when compared to other viral respiratory illnesses, such as influenza. While 82% of hospitalized patients with COVID-19 are ultimately discharged alive, median length of stay is 10-13 days. Early work in treating COVID-19 has focused on preventing worsening of the initial clinical presentation to prevent hospitalization and disease progression to organ failure and death. Studies conducted under this Master Host Tissue Protocol are expected to extend our knowledge of how to manage patients who are hospitalized for COVID-19 illness. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. This Master Protocol is a randomized, placebo-controlled trial of agents targeting the host response in COVID-19 in hospitalized patients with hypoxemia. The Master Host Tissue Protocol is designed to be flexible in the number of study arms, the use of a single placebo group, and the stopping and adding of new therapies. Our primary outcome is oxygen free days through day 28. This is defined as days alive and without supplemental oxygen use during the first 28 days following randomization. Patients who die on or before day 28 are assigned -1 oxygen free days.

Official Title
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International Sites: CONNECTS Master Protocol for Clinical Trials Targeting Macro-, Micro-immuno-thrombosis, Vascular Hyperinflammation, and Hypercoagulability and Renin-angiotensin-aldosterone System (RAAS) in Hospitalized Patients With COVID-19 (ACTIV-4 Host Tissue)

Conditions
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COVID-19, SARS-CoV2 Infection, Coronavirus Infection

Intervention / Treatment
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* Drug: Fostamatinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized for COVID-19 ≥18 years of age SARS-CoV-2 infection, documented by: nucleic acid test (NAT) or equivalent testing within 3 days prior to randomization OR documented by NAT or equivalent testing more than 3 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection per the responsible investigator (For non-NAT tests, only those deemed with equivalent specificity to NAT by the protocol team will be allowed. A central list of allowed non- NAT tests is maintained in Appendix E. Appendix E. Non-NAT Tests Deemed with Equivalent Specificity to NAT by the Protocol Team). Hypoxemia, defined as SpO2 <92% on room air, new receipt of supplemental oxygen to maintain SpO2 ≥92%, or increased supplemental oxygen to maintain SpO2 ≥92% for a patient on chronic oxygen therapy Symptoms or signs of acute COVID-19, defined as one or more of the following: cough reported or documented body temperature of 100.4 degrees Fahrenheit or greater shortness of breath chest pain infiltrates on chest imaging (x-ray, CT scan, lung ultrasound) Exclusion Criteria: Onset of COVID-19 symptom fulfilling inclusion criterion #5 >14 days prior to randomization Hospitalized with hypoxemia (as defined in inclusion #4) for >72 hours prior to randomization (the 72-hour window for randomization begins when the patient first meets the hypoxemia inclusion criteria after hospital admission) Pregnancy Breastfeeding Prisoners End-stage renal disease (ESRD) on dialysis Patient undergoing comfort care measures only such that treatment focuses on end-of- life symptom management over prolongation of life. The treating clinician expects inability to participate in study procedures or participation would not be in the best interests of the patient Known allergy/hypersensitivity to IMP or its excipients Fostamatinib Arm-Specific Exclusion Criteria: The following exclusion criteria differ from the master protocol criteria: 1. Randomized in another trial evaluating fostamatinib in the prior 30 days Study arm exclusion criteria measured within 24 hours prior to randomization: AST or ALT ≥ 5 × upper limit of normal (ULN) or ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN SBP > 160 mmHg or DBP > 100 mmHg at the time of screening and randomization ANC < 1000/mL Patient is anticipated to require a strong CYP3A inhibitor (Atazanavir, Certinib, Clarithromycin, Cobicistat and cobicistat-containing coformulations, Idelalisib,Indinavir, Itraconazole, Ketoconazole, Levoketoconazole, Lonafarnib, Lopinavir, Mifeprostone, Mibefradil, Nefazodone, Nelfinavir, Ombitasvir-paritaprevir-ritonavir plus dasabuvir, Posaconazole, Ribociclib Ritonavir, Saquinavir, Telithromycin, Troleandomycin, Tucatinib, Voriconazole) from randomization to 21 days post-randomization. For a full list of CYP3A4 substrates, please reference this regularly updated list: https://drug-interactions.medicine.iu.edu/MainTable.aspx. Patient unable to participate or declines participation in the fostamatinib arm.

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
Interventional Model Description: Participants will be randomly allocated in a two-step process: 1) The participant will first be randomized in an m:1 ratio to receive an active study drug or placebo, where m represents the number of study drug arms for which the participant is eligible. 2) The participant will then be randomly assigned with equal probability to one of the study drug arms. Participants will receive the corresponding study drug or matching placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fostamatinib<br>An investigational oral spleen tyrosine kinase inhibitor. | Drug: Fostamatinib<br>* Fostamatinib100-150mg orally twice daily for 14 days or 28 doses. Study medication will be continued as an outpatient if the patient is discharged prior to completing 28 doses.<br>|
| Placebo Comparator: Placebo<br>Orange film-coated, plain, bioconvex tablets for fostamatinib. For the purposes of interim and final analyses, the route and frequency of placebo will be ignored, and all placebo participants will be pooled together as a single group. In comparing an active drug versus placebo, only those placebo participants that were eligible for the active drug will be included. | Drug: Placebo<br>* Orange film-coated, plain bioconvex tablets orally twice daily for 14 days or 28 doses for fostamatinib. Study medication will be continued as an outpatient if the patient is discharged prior to completing 28 doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen free days through day 28 | This is defined as days alive and without supplemental oxygen use during the first 28 days following randomization. Patients who die on or before day 28 are assigned -1 oxygen free days. Patients will be considered to be receiving supplemental oxygen therapy when they are receiving any of the following: supplemental oxygen by nasal cannula, supplemental oxygen by face mask, high flow nasal cannula (HFNC), non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO). | Day 1 to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-hospital mortality | Proportion of patients who die during hospitalization | Day 1 to hospital discharge or Day 90 whichever comes first | 
| Alive and oxygen free at Day 14 | Proportion of patients oxygen free at day 14. Patients will be considered to be receiving supplemental oxygen therapy when they are receiving any of the following: supplemental oxygen by nasal cannula, supplemental oxygen by face mask, high flow nasal cannula (HFNC), non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO). | Day 1 to Day 14 | 
| Alive and oxygen free at Day 28 | Proportion of patients oxygen free at day 28. Patients will be considered to be receiving supplemental oxygen therapy when they are receiving any of the following: supplemental oxygen by nasal cannula, supplemental oxygen by face mask, high flow nasal cannula (HFNC), non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), or extracorporeal membrane oxygenation (ECMO) | Day 1 to Day 28 | 
| Alive and free of new invasive mechanical ventilation at day 28 | Proportion of patients alive free of new invasive mechanical ventilation at day 28 | Day 1 to Day 28 | 
| 28-day mortality | Proportion of patients alive at Day 28 | Day 28 | 
| 60-day mortality | Proportion of patients alive at Day 60 | Day 60 | 
| 90-day mortality | Proportion of patients alive at Day 90 | Day 90 | 
| Clinical status assessed using World Health Organization (WHO) 8-point ordinal scale at Day 14 | Ambulatory - Not hospitalized and no limitation of activities Ambulatory - Not hospitalized with limitation of activities or home oxygen use Hospitalized Mild Disease - Hospitalized, no oxygen therapy Hospitalized Mild Disease - Hospitalized, oxygen by mask or nasal prongs Hospitalized Severe Disease - Non-invasive ventilation or high-flow nasal cannula Hospitalized Severe Disease -Invasive mechanical ventilation Hospitalized Severe Disease - Invasive mechanical ventilation plus additional organ support with- vasopressors, RRT, or ECMO Dead | Day 14 | 
| Clinical status assessed using WHO 8-point ordinal scale at Day 28 | Ambulatory - Not hospitalized and no limitation of activities Ambulatory - Not hospitalized with limitation of activities or home oxygen use Hospitalized Mild Disease - Hospitalized, no oxygen therapy Hospitalized Mild Disease - Hospitalized, oxygen by mask or nasal prongs Hospitalized Severe Disease - Non-invasive ventilation or high-flow nasal cannula Hospitalized Severe Disease -Invasive mechanical ventilation Hospitalized Severe Disease - Invasive mechanical ventilation plus additional organ support with- vasopressors, RRT, or ECMO Dead | Day 28 | 
| Clinical status assessed using WHO 8-point ordinal scale at Day 60 | Ambulatory - Not hospitalized and no limitation of activities Ambulatory - Not hospitalized with limitation of activities or home oxygen use Hospitalized Mild Disease - Hospitalized, no oxygen therapy Hospitalized Mild Disease - Hospitalized, oxygen by mask or nasal prongs Hospitalized Severe Disease - Non-invasive ventilation or high-flow nasal cannula Hospitalized Severe Disease -Invasive mechanical ventilation Hospitalized Severe Disease - Invasive mechanical ventilation plus additional organ support with- vasopressors, RRT, or ECMO Dead | Day 60 | 
| Hospital-free days through day 28 | Days alive and not hospitalized during the first 28 days following randomization. Patients who die on or before day 28 are assigned a value -1. | Day 1 to Day 28 | 
| Ventilator-free days through day 28 | Days alive and not receiving mechanical ventilation during the first 28 days following randomization. Patients who die on or before day 28 are assigned a value -1. | Day 1 to Day 28 | 
| Respiratory failure-free days through day 28 | Days alive and not in respiratory failure during the first 28 days following randomization. A respiratory failure-free day is defined as a day alive without the use of HFNC, NIV, IMV, or (ECMO). Patients who die on or before day 28 are assigned a value -1. | Day 1 to Day 28 |