Immune Modulators for Treating COVID-19

Inclusion Criteria:

1. Admitted to a hospital or awaiting admission in the ED with symptoms suggestive ofCOVID-19.
2. Subject (or legally authorized representative) provides informed consent prior toinitiation of any study procedures.
3. Subject (or legally authorized representative) understands and agrees to comply withplanned study procedures.
4. Male or non-pregnant female adults ≥18 years of age at time of enrollment.
5. Has laboratory-confirmed (within 14 days prior to enrollment) SARS-CoV-2 infection asdetermined by PCR or other commercial or public health assay in any specimen.
6. Ongoing illness of any duration, and at least one of the following:

• Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
• Blood oxygen saturation (SpO2) ≤94% on room air, OR
• Requiring supplemental oxygen, OR
• Requiring mechanical ventilation or ECMO.

7. Women of childbearing potential must agree to either abstinence or use of at least oneprimary form of contraception not including hormonal contraception from the time ofscreening through Day 60.
8. Agrees to not to participate in another interventional trial for the treatment ofCOVID-19 through Day 60. Exception 1: Participant may co-enroll in ACTIV-4 (ACTIV-4A and ACTIV-4C). Exception 2:Participants in ACTIV-2 who have been hospitalized may be enrolled in ACTIV-1 as long asACTIV-2 study therapy has been discontinued. They will remain in ACTIV-2 follow-up. Exception 3: If participant is already participating in a COVID-19 vaccine trial butdevelops COVID-19 disease that requires hospitalization, participant is eligible for thisstudy, assuming all other inclusion/exclusion criteria are met.

Exclusion Criteria:

1. ALT or AST >10 times the upper limit of normal.
2. Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receivinghemodialysis or hemofiltration). Exception: Participants with an eGFR <30 mL/min may enroll as long as their renalinsufficiency has been stable without renal replacement therapy for ≥1 month and theyare not current candidates for renal replacement therapy. These participants will notreceive remdesivir.
3. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L).
4. Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L)
5. Pregnancy or breast feeding.
6. Anticipated discharge from the hospital or transfer to another hospital which is not astudy site within 72 hours.
7. Known allergy to any study medication.
8. Received cytotoxic or biologictargeted immune-modulator treatments (such asanti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], anti-IL-17, or T-cellor B-cell targeted therapies ([e.g., rituximab), tyrosine kinase], JAK inhibitors [including baricitinib,], TNF inhibitors, or interferon) within 4 weeks or 5half-lives prior to screening., whichever is longer. Steroid dependency, defined asneed for prednisone at a dose >10 mg (or equivalent) for >1 month within 2 weeks ofscreening, is exclusionary. Note Exception 1: Dexamethasone (at a dose of 6 mg per dayfor up to 10 days) is permitted for the treatment of COVID-19 in patients who arealready mechanically ventilated and in patients who require supplemental oxygen atscreening, but who are not mechanically ventilated in accordance with nationalguidelines. Note Exception 2: Infusion of convalescent plasma given for treatment ofCOVID-19 while on-study is also allowed. Exception 3: Monoclonal antibody therapy given for COVID-19 treatment at any timeprior to enrollment is also allowed.
9. BasedKnown or suspected history of untreated tuberculosis (TB). TB diagnosis may besuspected based on medical history and concomitant therapies that would suggest TBinfection, have suspected clinical diagnosis of current active tuberculosis (TB) or,if. Participants are also excluded if they have known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by historyonly, no screening required).
10. Based on medical history and concomitant therapies that would suggest infection,Knownor suspected serious, active bacterial, fungal, or viral (infection (exceptingSARS-CoV-2 and including, but not limited to, active HBV, HCV, or HIV/AIDS). with thelatter defined as a CD4 count <200 or an unsuppressed HIV viral load), or otherinfection (besides COVID-19) that in the opinion of the investigator could constitutea risk when taking investigational product. Note: Broad-spectrum empiric antibiotic usage does not exclude participation.
11. Have received any live vaccine (that is,or live attenuated) within 3 months beforescreening, or intend to receive a live vaccine (or live attenuated) during the study.Note Exception: Use of prior non-live (inactivated) vaccinations is allowed for allparticipants, including any vaccine for COVID-19.
12. Severe hepatic impairment (defined as liver cirrhosis Child stage C).
13. CurrentKnown severe heart failure (New York Heart Association [NYHA] III-IV).) ornew-onset left-systolic or global cardiac dysfunction in the setting of COVID-19. Exception: Right-sided heart dysfunction or pulmonary hypertension thought related toCOVID-19 is permitted.
14. In the Investigator's judgment, the patient has any advanced organ dysfunction thatwould not make participation appropriate.