CONNECTS Master Protocol for Clinical Trials targeting Macro- and Micro-Immuno-Thrombosis, Vascular Hyperinflammation, and Hypercoagulability and Renin-Angiotensin-Aldosterone System (RAAS) in Hospitalized Patients with COVID-19 (ACTIV-4 Host Tissue)

ACTIV 4 Host Tissue is a shared-placebo clinical trial platform evaluating therapies targeting the host response to COVID-19 in hospitalized patients. The overarching goal of the platform was 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. Three trials were implemented to investigate three agents: TXA-127, TRV-027, and Fostamatinib. These agents all impact the host tissue response in COVID-19 via a number of unique mechanisms, including potential beneficial effects on the RAAS system and formation of neutrophil extracellular traps (NETs). Each trial evaluated the efficacy of these agents' ability to impact the host tissue response and improve outcomes in patients hospitalized with COVID-19. We found no evidence that any of the three agents significantly improved clinical outcomes as measured by the primary outcome, oxygen free days through day 28. ]]>
Platform-Wide Inclusion Criteria: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 ORDocumented 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: "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 therapySymptoms or signs of acute COVID-19, defined as one or more of the following:CoughReported or documented body temperature of 100.4o F or greaterShortness of breathChest painInfiltrates on chest imaging (X-Ray, CT scan, lung ultrasound) Platform-Wide Exclusion Criteria:Onset of COVID-19 symptoms fulfilling inclusion criterion #5 >14 days prior to randomizationHospitalized 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)PregnancyBreastfeedingPrisonersEnd-stage renal disease (ESRD) on dialysisPatient 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 patientKnown allergy/hypersensitivity to IMP or its excipients Additional TXA-127 Exclusion Criteria: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 Additional TRV-027 Exclusion Criteria:Participants on ARBs will be excluded from this study arm.Patient unable to participate or declines participation in the TRV027 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 Additional Fostamatinib 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.Randomized in another trial evaluating fostamatinib in the prior 30 days ]]>