ACTIV‐1 IM.

Methods	Drug name: infliximab, abatacept, remdesivir, cenicriviroc Trial design: randomised, parallel assignment, masking: triple (participant, investigator, outcome assessor) NCT number: NCT04593940 Target sample size: 2160 participants Planned completion date: September 2021
Participants	Setting Inpatient Multicentre, USA Eligibility criteria Inclusion criteria Admitted to a hospital or awaiting admission in the ED with symptoms suggestive of COVID‐19 Participant (or LAR) provides informed consent prior to initiation of any study procedures Participant (or LAR) understands and agrees to comply with planned study procedures Male or non‐pregnant female adults ≥ 18 years of age at time of enrolment Has laboratory‐confirmed (within 14 days prior to enrolment) 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.) SpO2 ≤ 94% on room air requiring supplemental oxygen requiring mechanical ventilation or ECMO WOCBP must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through day 60 Agrees to not participate in another intervention trial for the treatment of COVID‐19 through day 60 Exclusion criteria: ALT or AST > 5 times the ULN Estimated glomerular filtration rate (eGFR) < 30 mL/min (including patients receiving haemodialysis or hemofiltration) 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 breastfeeding 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 biologic treatments (such as anti‐interleukin‐1, anti‐IL‐6 (tocilizumab or sarilumab), IL‐17, or T‐cell‐ or B‐cell‐targeted therapies (e.g. rituximab), tyrosine kinase inhibitors including baricitinib, TNF inhibitors, or interferon within 4 weeks or 5 half‐lives prior to screening Suspected clinical diagnosis of current active tuberculosis (TB) or latent TB treated for < 4 weeks Based on medical history and concomitant therapies that would suggest infection, suspected serious, active bacterial, fungal, viral (including, but not limited to, active HBV, HCV, or HIV/AIDS) Live vaccine (that is, live attenuated) within 3 months before screening Severe hepatic impairment (defined as liver cirrhosis Child stage C) Current severe heart failure (NYHA III‐IV) In the investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate
Interventions	Intervention Infliximab (single dose, IV infusion, 5 mg/kg) Abatacept (single dose, IV infusion, 10 mg/kg) Remdesivir (removed) Cenicriviroc (loading dose: 450 mg (300 mg morning and 150 mg evening, day 2‐29: 300 mg) Comparator Placebo
Outcomes	Efficacy outcomes All‐cause mortality at up to 30 days: not planned at up to 60 days: not planned Clinical progression/improvement of symptoms: planned Length of hospital stay: planned as time to recovery Admission to ICU: not planned Length of ICU stay: not planned Quality of life, including fatigue: not planned Viral clearance: not planned Safety outcomes Number of participants with grade 3 and grade 4 AEs: planned Number of participants with SAEs: planned Additional study outcomes Number of participants with changes in abnormal WBC counts
Notes	Funding: National Center for Advancing Translational Science (NCATS) and Biomedical Advanced Research and Development Authority