Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial

Nafamostat continuous IV infusion for 7 days or until day of hospital discharge at a dose of 0.2mg/kg/hour. No adjustment in dose is needed for renal impairment, including for renal dialysis. The daily dose of nafamostat should be administered in 500 mL (rate of infusion 20.8 mL/hour) of normal saline. Normal saline is recommended (due to the tendency for patients with COVID-19 towards hyponatraemia) but not mandated, and 5% dextrose would be acceptable if felt clinically appropriate.

"Patients will be administered either a standard dose, intermediate dose or therapeutic anticoagulation of low molecular weight heparin (depending on assigned arm), choice of agent according to availability and local practice at the participating site.~The maximum dose of Enoxaparin will be 1mg/kg q12h or 1.5mg/kg q24h."

"Patients will be administered either a standard dose, intermediate dose or therapeutic anticoagulation of low molecular weight heparin (depending on assigned arm), choice of agent according to availability and local practice at the participating site.~The maximum dose of Dalteparin will be 100IU/kg q12h or 200IU/kg q24h."

"Patients will be administered either a standard dose, intermediate dose or therapeutic anticoagulation of low molecular weight heparin (depending on assigned arm), choice of agent according to availability and local practice at the participating site.~The maximum dose of Tinzaparin will be 175IU/kg q24h (not available within Australia)."

2 doses of 30mL (3x10mL vials) of COVID-19 Hyper-Immunoglobulin (Human) given over 2 days within 48 hours of randomisation. Three vials will have approximately 10500 AU of neutralising antibodies, equivalent to approximately 200mL of convalescent plasma

The dose of nirmatrelvir-ritonavir is dependent on renal function. Participants will receive 100mg BD of Ritonavir and either 150mg BD (if eGFR 30-59 mL/min/1.73m2) or 300mg BD (eGFR = 60 mL/min/1.73m2) of Nirmatrelvir. Investigators are advised to consider withholding treatment if participant's eGFR \< 30 mL/min/1.73m2.

The dose of intravenous remdesivir is 200 mg on day 1 followed by 100 mg daily for a further four doses (i.e., for five doses in total) or until hospital discharge, whichever occurs first. Remdesivir will be administered as an intravenous infusion via a central or peripheral venous catheter over a 30-120 minute period, as per local practice.