Novel Experimental COVID-19 Therapies Affecting Host Response

NCT04924660 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 210982
• Study Type: interventional
• Target: 1,060
• Locations: 1 country
• Sites: 51

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.

Conditions

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

Keywords

COVID-19 drug treatment; RAAS

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• In-hospital Mortality

  Day 1 to hospital discharge or Day 90 whichever comes first

• Alive and Oxygen Free at Day 14

  Day 1 to Day 14

• Alive and Oxygen Free at Day 28

  Day 1 to Day 28

• Alive and Free of New Invasive Mechanical Ventilation at Day 28

  Day 1 to Day 28

• 28-day Mortality

  Day 28

Other Outcomes (3)

• Hypotension

  Day 0 to Day 5 or hospital discharge whichever comes first

• Allergic Reaction

  Day 0 to Day 5 or hospital discharge whichever comes first

• Incident Renal Replacement Therapy During Hospitalization

  Day 0 to Day 5 or hospital discharge whichever comes first

Study Arms (4)

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

EXPERIMENTAL

An investigational peptide agonist of Mas receptors.

Drug: TXA127

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

EXPERIMENTAL

An investigational peptide biased agonist of the AT1 receptor.

Drug: TRV027

Placebo

PLACEBO COMPARATOR

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

Fostamatinib

EXPERIMENTAL

An investigational oral spleen tyrosine kinase inhibitor.

Drug: Fostamatinib

Interventions

TXA127 DRUG

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

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

TRV027 DRUG

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

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

Placebo 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.

Placebo

Fostamatinib 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.

Fostamatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Hospitalized for COVID-19
• ≥18 years of age
• SARS-CoV-2 infection, documented by:
• a 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)

You may not qualify if:

• 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
• Patient unable to participate or declines participation in the TXA127/Ang(1-7) arm.
• 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)
• 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.
• Known severe renal artery stenosis.
• Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis.
• Randomized in another trial evaluating RAAS modulation in the prior 30 days
• Participants on ARBs will be excluded from this study arm.
• Patient unable to participate or declines participation in the TRV027 arm.

Sponsors & Collaborators

• Sean Collins: lead
• National Institutes of Health (NIH): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (51)

University of Alabama Birmingham

Birmingham, Alabama, 35249, United States

Location

Chandler Regional Medical Center

Chandler, Arizona, 85224, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

University of Colorado Hospital

Aurora, Colorado, 80010, United States

Location

Denver Health Medical Center

Denver, Colorado, 80204, United States

Location

Yale University

New Haven, Connecticut, 06510, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

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

Miami, Florida, 33136, United States

Location

Ponce de Leon Clinical Research Site

Atlanta, Georgia, 30303, United States

Location

Emory Johns Creek

Atlanta, Georgia, 30322, United States

Location

Emory St. Joseph's Hospital

Atlanta, Georgia, 30342, United States

Location

Alexian Brothers Medical Center

Elk Grove Village, Illinois, 60007, United States

Location

AMITA Health St. Alexius Medical Center

Hoffman Estates, Illinois, 60169, United States

Location

Our Lady of the Lake Regional Medical Center

Baton Rouge, Louisiana, 70808, United States

Location

Ochsner Clinic Foundation

New Orleans, Louisiana, 70121, United States

Location

Johns Hopkins Bayview Medical Center

Baltimore, Maryland, 21224, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Jadestone Clinical Research, LLC

Silver Spring, Maryland, 20904, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02072, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Newton-Wellesley Hospital

Newton, Massachusetts, 02462, United States

Location

Baystate Health

Springfield, Massachusetts, 01119, United States

Location

Hennepin County Medical Center

Minneapolis, Minnesota, 55415, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, 87106, United States

Location

Mount Sinai Hospital

New York, New York, 10029, United States

Location

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Montefiore Medical Center Weiler Campus

The Bronx, New York, 10461, United States

Location

Montefiore Medical Center Moses Campus

The Bronx, New York, 10467, United States

Location

University of North Carolina Medical Center

Chapel Hill, North Carolina, 27514, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Cleveland Clinic Akron General

Akron, Ohio, 44321, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45229, United States

Location

Cleveland Clinic Fairview Hospital

Cleveland, Ohio, 44111, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

West Chester Hospital

West Chester, Ohio, 45069, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Temple University Hospital

Philadelphia, Pennsylvania, 19140, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37203, United States

Location

University of Texas, Houston

Houston, Texas, 77030, United States

Location

Intermountain Medical Center

Murray, Utah, 84107, United States

Location

University of Utah Health

Salt Lake City, Utah, 84108, United States

Location

UVA Health

Charlottesville, Virginia, 22908, United States

Location

Sentara Norfolk General Hospital

Norfolk, Virginia, 23507, United States

Location

VCU Health

Richmond, Virginia, 23298, United States

Location

Harborview Medical Center/University of Washington

Seattle, Washington, 98104, United States

Location

Related Publications (2)

• 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.

  PMID: 39625722 DERIVED

• 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.

  PMID: 37039791 DERIVED

MeSH Terms

Conditions

COVID-19; Coronavirus Infections

Interventions

angiotensin I (1-7); Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH; fostamatinib

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Sean P. Collins, MD
• Organization: Vanderbilt University Medical Center

vcc@vumc.org

615-343-8010

Study Officials

• Sean P. Collins, M.D.

  Vanderbilt University Medical Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Which study drug arm the participant enters will be known to the research sites and the participants, but assignment to active versus placebo will be blinded. The randomized assignment, concealed from the research team, will be transmitted to the site pharmacy, who will provide study medication. The participant, treating clinicians, study personnel (other than the unblinded statistician who will prepare closed DSMB interim reports), and outcome assessors will all remain blinded to group assignment until after the database is locked and blinded analysis is completed.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Emergency Medicine

Model Details: 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. Results data includes data from NCT05593770.

Study Record Dates

• First Submitted: June 9, 2021
• First Posted: June 14, 2021
• Study Start: July 15, 2021
• Primary Completion: October 25, 2023
• Study Completion: December 31, 2023
• Last Updated: January 22, 2025
• Results First Posted: January 22, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (51)