ACTT‐4.

Methods	Drug name: baricitinib, dexamethasone, remdesivir Trial design: multicenter, adaptive, randomised blinded controlled trial Identifiers: NCT04640168 Target sample size: 1500 participants Planned completion date: June 2021
Participants	Setting Inpatient Multicentre: USA, Japan, Republic of Korea, Mexico, Singapore Eligibility criteria Inclusion criteria Hospitalised with symptoms suggestive of COVID‐19 Participant (or LAR) provides informed consent prior to initiation of any study procedures and understands and agrees to comply with planned study procedures Male or non‐pregnant female adult ≥ 18 years of age at time of enrolment Illness of any duration and has laboratory‐confirmed SARS‐CoV‐2 infection as determined by PCR or other commercial or public health assay (e.g. NAAT, antigen test) in any respiratory specimen or saliva ≤ 14 days prior to randomisation Within the 7 days prior to randomisation requiring new use of supplemental oxygen (or increased oxygen requirement if on chronic oxygen) and requires at the time of randomisation low‐ or high‐flow oxygen devices or use of non‐invasive mechanical ventilation (ordinal scale category 5 or 6) 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 29 Agrees not to participate in another blinded clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID‐19 through day 29 Exclusion criteria Prior enrolment in ACTT‐3 or ACTT‐4 On invasive mechanical ventilation at the time of randomisation (ordinal scale category 7) Anticipated discharge from the hospital or transfer to another hospital that is not a study site within 72 h of randomisation Positive test for influenza virus during the current illness Received ≥ 5 doses of remdesivir including the loading dose, outside of the study as treatment for COVID‐19 Pregnancy or breastfeeding  Allergy to any study medication Received convalescent plasma or IVIg for COVID‐19, small molecule tyrosine kinase inhibitors, mAbs targeting cytokines, mAbs targeting T‐cells or B‐cells as treatment for COVID‐19 Use of probenecid that cannot be discontinued at study enrolment Received > 1 dose of dexamethasone ≥ 6 mg (or equivalent for other glucocorticoids) in the 7 days prior to time of randomisation Received ≥ 20 mg/day of prednisone (or equivalent for other glucocorticoids) for ≥ 14 consecutive days in the 4 weeks prior to screening Have diagnosis of current active or latent tuberculosis, if known, treated for < 4 weeks with appropriate therapy (by history only, no screening required) Serious infection (besides COVID‐19), immunosuppressive state, or immunosuppressive medications that in the opinion of the investigator could constitute a risk when taking baricitinib or dexamethasone Live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to receive a live vaccine (or live attenuated) during the study
Interventions	Intervention Remdesivir Baricitinib Dexamethasone Comparator Placebo
Outcomes	Efficacy outcomes All‐cause mortality at up to 30 days: planned at up to 60 days: not planned Clinical progression/improvement of symptoms: planned Length of hospital stay: planned 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 Change from baseline in ALT, AST, C‐reactive protein, creatinine, d‐dimer concentration, glucose, haemoglobin, platelets, prothrombin time, total bilirubin, WBC count Desirability of Outcome Ranking (DOOR) Time to recovery
Notes	Funding: NIAID