PROTECT-APT 1: Early Treatment and Post-Exposure Prophylaxis of COVID-19 (PROTECT-APT 1)

Population A: Symptomatic adults seeking care or testing for COVID-19 Inclusion Criteria: Age ≥ 18 years Positive molecular or antigen diagnostic test for SARS-CoV-2 at study enrollment or within ≤ 5 days prior to enrollment Presence of two or more Screening Symptoms listed in Supplement 3 with at least two symptoms classified as moderate to severe (and/or ≥ 2 on the frequency questions or loss of taste/smell questions) at the time of enrollment For participants who have preexisting conditions causing mild or moderate symptoms listed on the Screening Symptom Questionnaire, there must be an increase of at least one severity level for that symptom at enrollment (For example, prior to illness participant routinely experienced headaches rated as moderate severity, now rating headache as severe at enrollment) Supplement 3 Screening Symptoms: stuffy or runny nose, hoarse voice, sore throat, difficulty breathing, cough, fatigue (low energy or tiredness), muscle or body aches, headache, fever (documented temperature > 38° C [100.4° F]) or subjective fever, chills or shivering, feeling hot or feeverish, nausea, vomiting, diarrhea, loss of smell, loss of taste Symptom onset ≤ 5 days prior to enrollment Exclusion Criteria: Hospital admission at the time of enrollment Hospitalization will be defined as requiring medical care not available in an outpatient setting for greater than 24 hours Hospitalization for isolation or quarantine requirements or for social reasons will NOT constitute an exclusion criterion Laboratory confirmed SARS-CoV-2 infection 6 to 90 days prior to enrollment Oxygen saturation < 92% on room air Baseline use of supplemental oxygen at the time of enrollment Presence of ≥ 1 of the following comorbidities that per the PI puts the patient at increased risk of developing severe COVID-19 illness: ≥65 years of age; BMI >25 kg/m2; chronic lung, liver, cardiovascular, kidney, or sickle cell disease; diabetes; cancer; neurodevelopmental disorders Immunocompromised: HIV infection with CD4 cell count <200 mm3 and/or VL ≥1,000 copies/mL; patients receiving immunosuppressive therapy including cytotoxic agents or systemic corticosteroids (≥20 mg/day of prednisone po or IV (or other equivalent glucocorticoids) for ≥14 consecutive days in the 4 weeks prior to screening); organ or bone marrow transplant Population B: Uninfected adult contacts of symptomatic SARS-CoV-2 infected individuals Inclusion Criteria: Age ≥ 18 years Asymptomatic contact of an individual with laboratory confirmed SARS-CoV-2 infection defined as: Exposure to the symptomatic case or cases within 6 feet (2 meters) for ≥ 15 minutes over a 24-hour period without the use of personal protective equipment Negative screening SARS-CoV-2 molecular or antigen diagnostic test performed at screening or within less than or equal to 24 hours of enrollment Exposure and enrollment within 6 days or less from when the symptomatic, confirmed SARS-CoV-2 positive case first had symptoms Exclusion Criteria: 1. Symptoms attributed to COVID-19 as assessed by the investigator 2. Positive molecular or antigen diagnostic test for SARS-CoV-2 from any upper respiratory specimen within 90 days prior to enrollment 3. SARS-CoV-2 vaccination within 90 days prior to enrollment EXCEPT if severely immunocompromised or a known vaccine non-responder Severely immunocompromised or a known vaccine non-responder defined as: solid organ or stem cell transplant recipient, B cell leukemia, receiving B cell depletion therapy (e.g., rituximab), agammaglobulinemia, or negative serology ≥2 weeks after vaccination with two doses of a vaccine 5. Hospital admission at the time of enrollment Hospitalization will be defined as requiring medical care not available in an outpatient setting for greater than 24 hours Hospitalization for isolation or quarantine requirements or for social reasons will NOT constitute an exclusion criterion For Both populations: Inclusion Criteria: 1. Must also meet the intervention specific inclusion/exclusion criteria for at least one PSA that is enrolling participants Exclusion Criteria: Absence of informed consent Pregnancy Breastfeeding Individuals who the study investigators believe are unable to comply with the requirements of the study Participation in another intervention trial for the treatment or prophylaxis of SARS-CoV-2 infection or COVID-19 disease at the time of enrollment Women of childbearing potential must agree to use an effective contraceptive method upon enrollment in the study through three months after the last dose of the investigational product. A woman is considered of childbearing potential unless post-menopausal (subject is at least 50 years old and has history of ≥ 2 years without menses without other known or suspected cause and has a FSH level >40 IU/L), or permanently surgically sterilized. Additional Exclusion Criteria for the Early Treatment Upamostat Arm: Patient is currently taking or is expected to start taking warfarin, apixaban (Eliquis), or rivaroxaban (Xarelto). Patients may be taking or start on study dabigatran (Pradaxa), standard or low molecular weight heparin. Patients with prolonged QT/QTc interval and/or increased susceptibility to arrythmia defined as the presence of any of the following: QTcF interval > 450 msec Pathological Q-waves (defined as Q-wave > 40 msec or depth > 0.4-0.5 mV) Evidence of ventricular pre-excitation Electrocardiographic evidence of complete LBBB, RBBB, incomplete LBBB, in complete RBBB Evidence of second- or third-degree heart block Intraventricular conduction delay with QRS duration > 120 msec Bradycardia as defined by sinus rate< 50 bpm Personal or family history of long QT syndrome Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, except for sinus arrhythmia Syncopal episodes or additional risk factors for torsades de points (e.g., heart failure, hypokalemia)