Purpose

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.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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 in the study protocol) 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 painTXA127-specific exclusion criter 5. infiltrates on chest imaging (x-ray, CT scan, lung ultrasound)

Exclusion Criteria

  1. COVID-19 symptom onset >14 days prior to randomization 2. Hospitalized for >72 hours prior to randomization 3. Pregnancy 4. Breastfeeding 5. Prisoners 6. End-stage renal disease (ESRD) on dialysis 7. Patient and/or clinical team is not pursuing full medical management (if a patient has a Do Not Resuscitate order that precludes chest compressions in the event of a cardiac arrest but is otherwise pursuing full medical management, he/she is eligible for this trial). 8. The treating clinician expects inability to participate in study procedures or participation would not be in the best interests of the patient The following exclusion criteria differ from the master protocol criteria: TXA127-specific exclusion criteria: 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: 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: 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 requires use of strong CYP3A modulators from Table above (Clarithromycin, Indinavir, Itraconazole, Ketoconazole, Nefazodone, Nelfinavir, Ritonavir, Saquinavir, Telithromycin, Troleandomycin, Carbamazepine, Efavirenz, Enzalutamide, Modafinil, Nevirapine, Oxcarbazepine, Phenobarbital, Phenytoin, Rifabutin, Rifampin, St. John's Wort, or Troglitazone). 5. Patient unable to participate or declines participation in the fostamatinib arm.

Study Design

Phase
Phase 2/Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention 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.
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
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.

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
TXA127
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
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.
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.

Recruiting Locations

Massachusetts General Hospital
Boston, Massachusetts 02114
Contact:
Michael Filbin, MD
617-724-0348
MFILBIN@mgh.harvard.edu

More Details

Status
Recruiting
Sponsor
Vanderbilt University Medical Center

Study Contact

Sheri L. Dixon, B.S.N., R.N.
615-343-0266
sheri.dixon@vumc.org

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.