Population A: Symptomatic adults seeking care or testing for COVID-19

Inclusion Criteria:

1. Age ≥ 18 years

2. Positive molecular or antigen diagnostic test for SARS-CoV-2 at study enrollment or
within ≤ 5 days prior to enrollment

3. 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 a. 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 feverish, nausea,
vomiting, diarrhea, loss of smell, loss of taste

4. Symptom onset ≤ 5 days prior to enrollment

Exclusion Criteria:

1. Hospital admission at the time of enrollment

2. Hospitalization will be defined as requiring medical care not available in an
outpatient setting for greater than 24 hours

3. Hospitalization for isolation or quarantine requirements or for social reasons will
NOT constitute an exclusion criterion

4. Laboratory confirmed SARS-CoV-2 infection 6 to 90 days prior to enrollment

5. Oxygen saturation < 92% on room air

6. Baseline use of supplemental oxygen at the time of enrollment

7. Presence of any of the following comorbidities that per the PI puts the patient at
high risk of developing severe COVID-19 illness:

a. Age ≥ 75 years b. Active treatment for solid tumor and hematologic malignancies
c. Hematologic malignancy, myeloma, or related disorder (e.g., myelodysplastic
syndrome, myelofibrosis) d. Receipt of solid-organ transplant or an islet transplant
and taking immunosuppressive therapy e. Chemotherapy or radiotherapy for solid organ
cancer in the last 12 months f. Receipt of chimeric antigen receptor (CAR)-T-cell
therapy or hematopoietic stem cell transplant (within 2 years of transplantation or
taking immunosuppressive therapy) g. Moderate or severe primary immunodeficiency
(e.g., common variable immunodeficiency disease, severe combined immunodeficiency,
DiGeorge syndrome, Wiskott-Aldrich syndrome) h. Advanced or untreated HIV infection
(people with HIV and CD4 cell counts less than 200/mm3, history of an AIDS-defining
illness without immune reconstitution, or clinical manifestations of symptomatic
HIV) i. Active treatment with high-dose corticosteroids (i.e., 20 or more mg of
prednisone or equivalent per day when administered for 2 or more weeks), alkylating
agents, antimetabolites, transplant-related immunosuppressive drugs, cancer
chemotherapeutic agents classified as severely immunosuppressive, tumor necrosis
factor (TNF) blockers, and other biologic agents that are immunosuppressive or
immunomodulatory j. Sickle cell disease k. Chronic liver disease (e.g., Child-Pugh
Class A, B or C cirrhosis) l. Down syndrome m. Dementia or neurocognitive disability
(e.g., Parkinson's disease) n. Participants with 3 or more of the following
conditions: i) No prior COVID-19 infection OR has not completed a COVID-19 vaccine
series within the last 6 months OR has not received a vaccine booster within the
last 6 months ii) Age 65-74 years iii) BMI ≥35 (or >95th percentile in adolescents)
iv) Type 1 or type 2 diabetes mellitus v) Cardiovascular disease (including HTN if
age >55) vi) Chronic lung disease (including bronchiectasis, CF, COPD, ILD, PHTN,
PE, moderate-to-severe asthma) vii) Chronic kidney disease (eGFR <30)

8. Participants who are receiving or plan to receive anti-SARS-CoV-2 antivirals for
treatment of their COVID-19

Population B: Uninfected adult contacts of symptomatic SARS-CoV-2 infected individuals

Inclusion Criteria:

1. Age ≥ 18 years

2. Asymptomatic contact of an individual with laboratory confirmed SARS-CoV-2 infection
defined as:

a. Indoor 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

3. Negative screening SARS-CoV-2 molecular or antigen diagnostic test performed at
screening or within less than or equal to 24 hours of enrollment

4. 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 4. 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

1. Hospitalization will be defined as requiring medical care not available in an
outpatient setting for greater than 24 hours 6. 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:

1. Absence of informed consent

2. Pregnancy

3. Breastfeeding

4. Individuals who the study investigators believe are unable to comply with the
requirements of the study

5. Participation in another intervention trial for the treatment or prophylaxis of
SARS-CoV-2 infection or COVID-19 disease at the time of enrollment

Additional Criteria for the Early Treatment Upamostat Arm:

Inclusion Criteria:

1. Women of childbearing potential must agree to use an effective contraceptive
method upon enrollment in the study through 8 weeks after the last dose of the
investigational product. This would include oral contraceptives, implanted
contraceptives, intrauterine devices, and barrier methods.

- A woman is considered of childbearing potential unless post-menopausal (subject
is at least 50 years old and has a history of ≥ 2 years without menses without
other known or suspected cause), or permanently surgically sterilized.

- Participants not of reproductive potential are eligible without requiring the
use of a contraceptive method. Participant-reported history is acceptable
documentation of surgical sterilization and menopause.

Exclusion Criteria:

1. 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.

2. Patients with prolonged QT/QTc interval and/or increased susceptibility to
arrythmia defined as the presence of any of the following:

- QTc 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)