Novel Experimental COVID-19 Therapies Affecting Host Response (NECTAR)

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)

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; Coronavirus Infection; SARS-CoV-2 Infection
• Intervention / Treatment: Drug: Fostamatinib; Drug: TXA127; Drug: TRV027; Drug: Placebo

Detailed Description

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.

April 20, 2022 TRV027 and TXA127 arms closed to accrual.

• Study Type: Interventional
• Enrollment (Actual): 871
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Sheri L. Dixon, B.S.N., R.N.; Phone Number: 615-343-0266; Email: sheri.dixon@vumc.org
• Study Contact Backup: Name: Sean P. Collins, M.D.; Phone Number: 615-875-6151; Email: sean.collins@vumc.org

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama Birmingham
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Chandler Regional Medical Center
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80010
      • University of Colorado Hospital
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Miami, Florida, United States, 33136
      • Public Health Trust of Miami-Dade County, Florida - Jackson Memorial Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Emory St. Joseph's Hospital
    • Atlanta, Georgia, United States, 30303
      • Ponce de Leon Clinical Research Site
    • Atlanta, Georgia, United States, 30322
      • Emory Johns Creek
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Medical Center
    • Hoffman Estates, Illinois, United States, 60169
      • AMITA Health St. Alexius Medical Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Our Lady of the Lake Regional Medical Center
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview Medical Center
    • Silver Spring, Maryland, United States, 20904
      • Jadestone Clinical Research, LLC
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02072
      • Beth Israel Deaconess Medical Center
    • Newton, Massachusetts, United States, 02462
      • Newton-Wellesley Hospital
    • Springfield, Massachusetts, United States, 01119
      • Baystate Health
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Health Sciences Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center Weiler Campus
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center Moses Campus
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Akron, Ohio, United States, 44321
      • Cleveland Clinic Akron General
    • Cincinnati, Ohio, United States, 45229
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Fairview Hospital
    • West Chester, Ohio, United States, 45069
      • West Chester Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas, Houston
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Health
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • UVA Health
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital
    • Richmond, Virginia, United States, 23298
      • VCU Health
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center/University of Washington

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria

1. Hospitalized for COVID-19
2. ≥18 years of age

3. SARS-CoV-2 infection, documented by:

   1. a nucleic acid test (NAT) or equivalent testing within 3 days prior to randomization OR
   2. 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).
4. 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

5. Symptoms or signs of acute COVID-19, defined as one or more of the following:

   1. cough
   2. reported or documented body temperature of 100.4 degrees Fahrenheit or greater
   3. shortness of breath
   4. chest pain
   5. infiltrates on chest imaging (x-ray, CT scan, lung ultrasound)

Exclusion criteria

1. Onset of COVID-19 symptom fulfilling inclusion criterion #5 >14 days prior to randomization
2. 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)
3. Pregnancy
4. Breastfeeding
5. Prisoners
6. End-stage renal disease (ESRD) on dialysis
7. Patient undergoing comfort care measures only such that treatment focuses on end-of-life symptom management over prolongation of life.
8. The treating clinician expects inability to participate in study procedures or participation would not be in the best interests of the patient
9. Known allergy/hypersensitivity to IMP or its excipients

The following exclusion criteria differ from the master protocol criteria:

TXA127-specific exclusion criteria(4/20/2022 Closed to Accrual):

1. Patient unable to participate or declines participation in the TXA127/Ang(1-7) arm.
2. History of sensitivity (including angioedema) or allergic reaction to medication targeting the RAAS system including study medications or other allergy in the opinion of the investigator that contraindicates participation (not applicable to fostamatinib arm)
3. Hemodynamic instability - defined as MAP < 65 mmHg at time of randomization confirmed on two measurements 5 minutes apart OR vasopressors at or above norepinephrine equivalent of 0.1 mcg/kg/min in prior 4 hours to maintain MAP > 65 mmHg.
4. Known severe renal artery stenosis.
5. Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis.
6. Randomized in another trial evaluating RAAS modulation in the prior 30 days

TRV027-specific exclusion criteria (4/20/2022 Closed to Accrual):

1. Participants on ARBs will be excluded from this study arm.
2. Patient unable to participate or declines participation in the TRV027 arm.
3. History of sensitivity (including angioedema) or allergic reaction to medication targeting the RAAS system including study medications or other allergy in the opinion of the investigator that contraindicates participation (not applicable to fostamatinib arm)
4. Hemodynamic instability - defined as MAP < 65 mmHg at time of randomization confirmed on two measurements 5 minutes apart OR vasopressors at or above norepinephrine equivalent of 0.1 mcg/kg/min in prior 4 hours to maintain MAP > 65 mmHg.
5. Known severe renal artery stenosis.
6. Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis.
7. Randomized in another trial evaluating RAAS modulation in the prior 30 days

Fostamatinib 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:

1. AST or ALT ≥ 5 × upper limit of normal (ULN) or ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
2. SBP > 160 mmHg or DBP > 100 mmHg at the time of screening and randomization
3. ANC < 1000/mL
4. 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.
5. Patient unable to participate or declines participation in the fostamatinib arm.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fostamatinib; An investigational oral spleen tyrosine kinase inhibitor.	Drug: Fostamatinib; 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.
Experimental: TXA127 (4/20/2022 Arm Closed to Accrual); An investigational peptide agonist of Mas receptors.	Drug: TXA127; TXA127 0.5 mg/kg/day infused 3 hours daily for 5 days or until hospital discharge whichever comes first.
Experimental: TRV027 (4/20/2022 Arm Closed to Accrual); An investigational peptide biased agonist of the AT1 receptor.	Drug: TRV027; TRV027 12mg/h as a continuous 24-hour infusion, infused for 5 days or until hospital discharge whichever comes first.
Placebo Comparator: Placebo; NaCl 0.9% infused to match the duration of the agent for TXA127, TRV027, and APN01. 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; NaCl 0.9% infused to match the duration of the agent (3 hours for TXA127 and continuous 24-hour infusion for TRV027, over 30 minutes for APN01. 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.

What is the study measuring?

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 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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal outcomes: acute kidney Injury (when possible, at participating sites)	Proportion of participants with evidence of acute kidney injury using the KDIGO Stage 2 criteria for serum creatinine relative to baseline at Day 0.	Day 0 to Day 5 or hospital discharge whichever comes first
Myocardial injury (when possible, at participating sites)	Proportion of participants with Myocardial injury described by changes in troponin before, during and after therapy during hospitalization.	Day 0 to Day 5 or hospital discharge whichever comes first
RAAS pathway mechanistic biomarkers (when possible and applicable, at participating sites)	Proportion of participants with changes in RAAS mechanistic biomarkers (AngII, Ang(1-7), ACE activity and ACE2 activity) before, during and after therapy during hospitalization.	Day 0 to Day 5 or hospital discharge whichever comes first
Trajectories of biomarkers related to COVID-19 (when possible, at participating sites)	Proportion of participants with changes in trajectories of biomarkers related to COVID-19	Day 0 to Day 5 or hospital discharge whichever comes first
Changes in NT-proBNP (when possible, at participating sites)	Proportion of participants with changes in NTproBNP before, during and after therapy during hospitalization.	Day 0 to Day 5 or hospital discharge whichever comes first
Hypotension	Proportion of participants with hypotension defined by low arterial blood pressure leading to either [1] initiation or increase in vasopressor therapy, [2] administration of a fluid bolus of 500 ml or more, or [3] modification of the dose or discontinuation of the study drug.	Day 0 to Day 5 or hospital discharge whichever comes first
Allergic reaction	Proportion of participants with allergic reaction, including rash and angioedema	Day 0 to Day 5 or hospital discharge whichever comes first
Incident renal replacement therapy during hospitalization (when possible, at participating sites)	Proportion of participants requiring renal replacement therapy	Day 0 to Day 5 or hospital discharge whichever comes first

Collaborators and Investigators

• Sponsor: Sean Collins
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH)
• Investigators: Study Chair: Sean P. Collins, M.D., Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2021
• Primary Completion (Actual): October 25, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: June 9, 2021
• First Submitted That Met QC Criteria: June 10, 2021
• First Posted (Actual): June 14, 2021

Study Record Updates

• Last Update Posted (Actual): January 23, 2024
• Last Update Submitted That Met QC Criteria: January 19, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: COVID-19 drug treatment; RAAS
• Additional Relevant MeSH Terms: Pathologic Processes; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; COVID-19; Coronavirus Infections; Infections; Communicable Diseases; Antihypertensive Agents; Vasodilator Agents; Angiotensin I (1-7)
• Other Study ID Numbers: 210982

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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