Novel Experimental COVID-19 Therapies Affecting Host Response

NCT ID: NCT04924660

Last Updated: 2025-01-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 1060 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-15
• Study Completion Date: 2023-12-31

Brief Summary

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. The primary analysis will include data from NCT05593770.

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.

Conditions

COVID-19; SARS-CoV-2 Infection; Coronavirus Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

TXA127 (4/20/2022 Arm Closed to Accrual)

An investigational peptide agonist of Mas receptors.

Group Type: EXPERIMENTAL

TXA127

Intervention Type: DRUG

TXA127 0.5 mg/kg/day infused 3 hours daily for 5 days or until hospital discharge whichever comes first.

TRV027 (4/20/2022 Arm Closed to Accrual)

An investigational peptide biased agonist of the AT1 receptor.

Group Type: EXPERIMENTAL

TRV027

Intervention Type: DRUG

TRV027 12mg/h as a continuous 24-hour infusion, infused for 5 days or until hospital discharge whichever comes first.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Fostamatinib

An investigational oral spleen tyrosine kinase inhibitor.

Group Type: EXPERIMENTAL

Fostamatinib

Intervention Type: DRUG

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.

Interventions

TXA127

TXA127 0.5 mg/kg/day infused 3 hours daily for 5 days or until hospital discharge whichever comes first.

Intervention Type: DRUG

TRV027

TRV027 12mg/h as a continuous 24-hour infusion, infused for 5 days or until hospital discharge whichever comes first.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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)

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

Exclusion Criteria

1. Onset of COVID-19 symptom fulfilling inclusion criterion #5 >14 days prior to randomization

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

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

1. Randomized in another trial evaluating fostamatinib in the prior 30 days

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Sean Collins

OTHER

Sponsor Role: lead

Responsible Party

Sean Collins

Professor, Emergency Medicine

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Sean P. Collins, M.D.

Role: STUDY_CHAIR

Vanderbilt University Medical Center

Locations

University of Alabama Birmingham

Birmingham, Alabama, United States

Chandler Regional Medical Center

Chandler, Arizona, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

Stanford University

Stanford, California, United States

University of Colorado Hospital

Aurora, Colorado, United States

Denver Health Medical Center

Denver, Colorado, United States

Yale University

New Haven, Connecticut, United States

University of Florida

Gainesville, Florida, United States

Public Health Trust of Miami-Dade County, Florida - Jackson Memorial Hospital

Miami, Florida, United States

Ponce de Leon Clinical Research Site

Atlanta, Georgia, United States

Emory Johns Creek

Atlanta, Georgia, United States

Emory St. Joseph's Hospital

Atlanta, Georgia, United States

Alexian Brothers Medical Center

Elk Grove Village, Illinois, United States

AMITA Health St. Alexius Medical Center

Hoffman Estates, Illinois, United States

Our Lady of the Lake Regional Medical Center

Baton Rouge, Louisiana, United States

Ochsner Clinic Foundation

New Orleans, Louisiana, United States

Johns Hopkins Bayview Medical Center

Baltimore, Maryland, United States

Johns Hopkins University

Baltimore, Maryland, United States

Jadestone Clinical Research, LLC

Silver Spring, Maryland, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Newton-Wellesley Hospital

Newton, Massachusetts, United States

Baystate Health

Springfield, Massachusetts, United States

Hennepin County Medical Center

Minneapolis, Minnesota, United States

Washington University

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, United States

Mount Sinai Hospital

New York, New York, United States

Columbia University Irving Medical Center

New York, New York, United States

Montefiore Medical Center Weiler Campus

The Bronx, New York, United States

Montefiore Medical Center Moses Campus

The Bronx, New York, United States

University of North Carolina Medical Center

Chapel Hill, North Carolina, United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

Cleveland Clinic Akron General

Akron, Ohio, United States

University of Cincinnati

Cincinnati, Ohio, United States

Cleveland Clinic Fairview Hospital

Cleveland, Ohio, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

West Chester Hospital

West Chester, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

Temple University Hospital

Philadelphia, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

University of Texas, Houston

Houston, Texas, United States

Intermountain Medical Center

Murray, Utah, United States

University of Utah Health

Salt Lake City, Utah, United States

UVA Health

Charlottesville, Virginia, United States

Sentara Norfolk General Hospital

Norfolk, Virginia, United States

VCU Health

Richmond, Virginia, United States

Harborview Medical Center/University of Washington

Seattle, Washington, United States

Countries

United States

References

Collins SP, Shotwell MS, Strich JR, Gibbs KW, de Wit M, Files DC, Harkins M, Hudock K, Merck LH, Moskowitz A, Apodaca KD, Barksdale A, Safdar B, Javaheri A, Sturek JM, Schrager H, Iovine NM, Tiffany B, Douglas I, Levitt J, Ginde AA, Hager DN, Shapiro N, Duggal A, Khan A, Lanspa M, Chen P, Gentile N, Harris E, Gong M, Sellers S, Goodwin AJ, Tidswell MA, Filbin M, Desai N, Gutierrez F, Estrada V, Burgos J, Boyles T, Pano-Pardo JR, Hussen N, Rosenberg Y, Troendle J, Bernard GR, Bistran-Hall AJ, Walsh K, Casey JD, DeClercq J, Joly MM, Pulley J, Rice TW, Schildcrout JS, Wang L, Semler MW, Self WH; ACTIV-4 Host Tissue Investigators. Fostamatinib for Hospitalized Adults With COVID-19 and Hypoxemia: A Randomized Clinical Trial. JAMA Netw Open. 2024 Dec 2;7(12):e2448215. doi: 10.1001/jamanetworkopen.2024.48215.

Reference Type: DERIVED

PMID: 39625722 (View on PubMed)

Self WH, Shotwell MS, Gibbs KW, de Wit M, Files DC, Harkins M, Hudock KM, Merck LH, Moskowitz A, Apodaca KD, Barksdale A, Safdar B, Javaheri A, Sturek JM, Schrager H, Iovine N, Tiffany B, Douglas IS, Levitt J, Busse LW, Ginde AA, Brown SM, Hager DN, Boyle K, Duggal A, Khan A, Lanspa M, Chen P, Puskarich M, Vonderhaar D, Venkateshaiah L, Gentile N, Rosenberg Y, Troendle J, Bistran-Hall AJ, DeClercq J, Lavieri R, Joly MM, Orr M, Pulley J, Rice TW, Schildcrout JS, Semler MW, Wang L, Bernard GR, Collins SP; ACTIV-4 Host Tissue Investigators. Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials. JAMA. 2023 Apr 11;329(14):1170-1182. doi: 10.1001/jama.2023.3546.

Reference Type: DERIVED

PMID: 37039791 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

210982

Identifier Type: -

Identifier Source: org_study_id