for people ages 18 years and up (full criteria)
at San Francisco, California and other locations
study started
estimated completion
Principal Investigator
by Michael Matthay, MD
Headshot of Michael Matthay
Michael Matthay



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.

Official Title

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 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.


COVID-19 SARS-CoV-2 Infection Coronavirus Infection COVID-19 drug treatment RAAS Infections Communicable Diseases Coronavirus Infections Angiotensin I (1-7) TXA127 TRV027 Fostamatinib APN01


You can join if…

Open to people ages 18 years and up

  1. Hospitalized for COVID-19
  2. ≥18 years of age
  3. SARS-CoV-2 infection, documented by:
  4. a nucleic acid test (NAT) or equivalent testing within 3 days prior to randomization OR
  5. 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)
  6. 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
  7. Symptoms or signs of acute COVID-19, defined as one or more of the following:
  8. cough
  9. reported or documented body temperature of 100.4 degrees Fahrenheit or greater
  10. shortness of breath
  11. chest pain
  12. infiltrates on chest imaging (x-ray, CT scan, lung ultrasound)

You CAN'T join if...

  1. 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
  2. COVID-19 symptom onset >14 days prior to randomization
  3. Hospitalized for >72 hours prior to randomization
  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. Pregnancy
  6. Breastfeeding
  7. Prisoners
  8. End-stage renal disease (ESRD) on dialysis
  9. 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).
  10. . Known severe renal artery stenosis
  11. . Known significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic or mitral stenosis
  12. . Randomized in another trial evaluating RAAS modulation in the prior 30 days
  13. . 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:

• Patient unable to participate or declines participation in the TXA127/Ang(1-7) arm.

TRV027-specific exclusion criteria:

  • Participants on ARBs will be excluded from this study arm.
  • Patient unable to participate or declines participation in the TRV027 arm.

Fostamatinib specific exclusion criteria:

  • 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 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).
  • Patient unable to participate or declines participation in the fostamatinib arm.

APN01 specific exclusion criteria:

• Patient unable to participate or declines participation in the APN01 arm


  • UCSF Medical Center - Parnassus not yet accepting patients
    San Francisco California 94143 United States
  • Stanford University accepting new patients
    Stanford California 94305 United States

Lead Scientist at UCSF

  • Michael Matthay, MD
    Professor, Medicine. Authored (or co-authored) 845 research publications.


accepting new patients
Start Date
Completion Date
Vanderbilt University Medical Center
Phase 2/3
Study Type
Last Updated