Immune Modulators for Treating COVID-19

ACTIV-1 IM is a master protocol designed to evaluate immune modulators for the treatment of moderately or severely ill hospitalized patients infected with COVID-19. Trial participants will be assessed daily while hospitalized. If the participants are discharged from the hospital prior to Day 29, they will have follow-up study visits at Days 8, 11, 15, 22, and 29. For discharged participants, it is preferred that the Day 8, 11, 15, and 29 visits are in person to obtain safety laboratory tests and blood (serum/plasma) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the participant to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The Day 60 assessment will be conducted by phone.

The effectiveness of each therapeutic agent as add-on therapy to SoC plus remdesivir (provided) will be evaluated based on the primary endpoint of time to recovery by Day 29. The sample size requirements are based on the ability to detect a moderate improvement in time to recovery (3-4 fewer days) for each agent. A total of 788 recoveries are required for each comparison to provide approximately 85% power to detect a recovery rate ratio of 1.25. Assuming 73% of participants achieve recovery in 28 days, consistent with the ACTT-1 results, the total sample size to evaluate 1, 2, and 3 agents in ACTIV-1 IM is approximately 1080, 1620, and 2160, respectively. Because each agent is being compared to SoC with no between-agent comparisons, no multiplicity adjustments for multiple agents are planned.

The CVC arm of the study was closed to enrollment on 3-Sep-2021.

Inclusion criteria

• Admitted to a hospital or awaiting admission in the ED with symptoms suggestive of COVID-19.
• Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
• Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
• Male or non-pregnant female adults ≥18 years of age at time of enrollment.
• Has laboratory-confirmed (within 14 days prior to enrollment) SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen.
• 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.
• Women of childbearing potential must agree to either abstinence or use of at least one primary form of contraception not including hormonal contraception from the time of screening through Day 60.
• Agrees to not to participate in another interventional trial for the treatment of COVID-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 as ACTIV-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 but develops COVID-19 disease that requires hospitalization, participant is eligible for this study, assuming all other inclusion/exclusion criteria are met.

Exclusion criteria

• ALT or AST >10 times the upper limit of normal.
• Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receiving hemodialysis or hemofiltration).

Exception: Participants with an eGFR <30 mL/min may enroll as long as their renal insufficiency has been stable without renal replacement therapy for ≥1 month and they are not current candidates for renal replacement therapy. These participants will not receive remdesivir.

• Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 103/μL or <1.0 GI/L).
• Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 103/μL or <0.20 GI/L)
• Pregnancy or breast feeding.
• Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
• Known allergy to any study medication.
• Received cytotoxic or biologictargeted immune-modulator treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], anti-IL-17, or T-cell or B-cell targeted therapies ([e.g., rituximab), tyrosine kinase], JAK inhibitors [including baricitinib,], TNF inhibitors, or interferon) within 4 weeks or 5 half-lives prior to screening., whichever is longer. Steroid dependency, defined as need for prednisone at a dose >10 mg (or equivalent) for >1 month within 2 weeks of screening, is exclusionary. Note Exception 1: Dexamethasone (at a dose of 6 mg per day for up to 10 days) is permitted for the treatment of COVID-19 in patients who are already mechanically ventilated and in patients who require supplemental oxygen at screening, but who are not mechanically ventilated in accordance with national guidelines. Note Exception 2: Infusion of convalescent plasma given for treatment of COVID-19 while on-study is also allowed.

Exception 3: Monoclonal antibody therapy given for COVID-19 treatment at any time prior to enrollment is also allowed.

• BasedKnown or suspected history of untreated tuberculosis (TB). TB diagnosis may be suspected based on medical history and concomitant therapies that would suggest TB infection, 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 history only, no screening required).
• Based on medical history and concomitant therapies that would suggest infection,Known or suspected serious, active bacterial, fungal, or viral (infection (excepting SARS-CoV-2 and including, but not limited to, active HBV, HCV, or HIV/AIDS). with the latter defined as a CD4 count <200 or an unsuppressed HIV viral load), or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.

Note: Broad-spectrum empiric antibiotic usage does not exclude participation.

• Have received any live vaccine (that is,or live attenuated) within 3 months before screening, 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 all participants, including any vaccine for COVID-19.
• Severe hepatic impairment (defined as liver cirrhosis Child stage C).
• CurrentKnown severe heart failure (New York Heart Association [NYHA] III-IV).) or new-onset left-systolic or global cardiac dysfunction in the setting of COVID-19.

Exception: Right-sided heart dysfunction or pulmonary hypertension thought related to COVID-19 is permitted.

• In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.