An International Multi-Centre Randomised Adaptive Platform Clinical Trial to Assess the Clinical, Virological and Immunological Outcomes in Patients with SARS-CoV-2 Infection (COVID-19).
ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled,
Bayesian, adaptive platform trial. The objective of ASCOT is to identify the regimen
(combination of interventions) associated with the highest chance of improving clinical
outcomes in adults hospitalised with COVID-19.
Platform trials allow multiple questions to be evaluated simultaneously and sequentially
within the platform, and evaluate interaction between different treatment options, to achieve
the goal of determining the optimal combination of treatments for the disease as rapidly as
possible. Study treatments are categorised into different treatment domains.
The adaptive nature of the trial means treatments within a domain or an entire domain can be
removed or added based on accruing data analysed at frequent intervals or based on external
evidence.
[Domain Closed] Intervention domain A (antiviral): Participants will be randomised to receive
either i) standard of care without nafamostat; or ii) standard of care with nafamostat
[Never Opened] Intervention domain B (antibody): Participants will be randomised to receive
either i) standard of care without hyperimmune globulin; or ii) standard of care with
hyperimmune globulin
[Domain Closed] Intervention domain C (anticoagulation): Participants will be randomised to
receive either i) standard dose thromboprophylaxis; or ii) intermediate dose
thromboprophylaxis; or iii) therapeutic anticoagulation
Intervention domain Q (Antiviral II):
Participants will be randomised to receive either i) no antiviral agents; or ii) oral
nirmatrelvir-ritonavir; or iii) intravenous remdesivir iiii) oral nirmatrelvir-ritonavir +
Intravenous remdesivir
Drug: (Arm Closed) Nafamostat Mesilate
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.
Other Name: Nafabelltan
Drug: (Arm Closed) Enoxaparin
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.
Drug: (Arm Closed) Dalteparin
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.
Drug: (Arm Closed) Tinzaparin
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).
Biological: (Arm Never Opened) Hyperimmune globulin
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
Drug: Nirmatrelvir-Ritonavir
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.
Other Name: Paxlovid
Drug: Remdesivir
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.
Other Name: Veklury
Inclusion Criteria:
A.Core Platform (all participants must meet the following):
1. Adult (as defined by local jurisdiction) patient admitted to hospital with acute illness
and suspected or proven SARS-CoV-2 infection.
B. Antiviral II Domain (all participants in the Antiviral II domain must meet the
following):
1. SARS-CoV-2 infection has been confirmed by positive rapid antigen test OR polymerase
chain reaction test within the last 7 days
Exclusion Criteria:
A. Core platform exclusions (all participants must not meet the following):
1. Death is deemed to be imminent and inevitable during the next 24 hours AND one or more
of the patient, substitute decision maker or attending physician are not committed to
full active treatment
2. Patient is expected to be discharged from hospital today or tomorrow
3. More than 14 days have elapsed while admitted to hospital with symptoms of an acute
illness due to proven SARS-CoV-2 infection
4. Previous participation in this trial, or another trial that is analysed within the
same statistical model as this trial, within the last 90 days
B. Antiviral II Domain exclusions (patients at sites participating in the Antiviral II
Domain must not meet the following):
1. Severe renal impairment, defined as eGFR<30ml/min or receipt of renal replacement
therapy
2. Severe hepatic impairment, defined as proven or suspected cirrhosis with Child Pugh
class of C, OR acute hepatitis, defined as AST or ALT>5 times the upper limit of
normal in the testing laboratory.
3. The patient has received, at the time of eligibility assessment, >24h of an antiviral
agent intended to have activity against SARS-CoV-2, within the past 7 days
4. The patient is known to be pregnant or breastfeeding
5. The treating clinician believes that participation in the domain would not be in the
best interests of the patient
B.1. Antiviral II Domain Non-Immune Suppressed Stratum-specific Exclusion Criteria (all
non-immune suppressed patients at sites participating in the Antiviral II Domain must not
meet the following):
1. Onset of COVID-related symptoms was more than 7 days (i.e., 168 hours) ago
B2. Antiviral II domain Intervention-specific Exclusion Criteria (All patients at sites
participating in the Antiviral II Domain will be excluded from the below interventions if
they meet the following):
Will be excluded from receiving Remdesivir if:
1. No venous access is available and none can be created
2. Known hypersensitivity to remdesivir or its excipients
Will be excluded from receiving Nirmatrelvir/ritonavir if:
1. The patient is unable to take, tolerate or absorb oral or enteral medications
2. Known hypersensitivity to any of nirmatrelvir, ritonavir or its excipients
3. Receipt of a concomitant drug with a high-risk interaction with nirmatrelvir-ritonavir
which cannot be ceased or substituted.
Will be excluded from receiving no antiviral agent if:
1. The patient is in the Immune Suppressed Stratum
2. The patient is receiving or has received supplemental oxygen on the calendar day of
eligibility assessment.
3. The patient is considered by the treating clinician to be at very high risk for
progression to severe COVID-19
Blacktown Hospital
Blacktown, New South Wales, Australia
Campbelltown Hospital
Campbelltown, New South Wales, Australia
St Vincent's Hospital Sydney
Darlinghurst, New South Wales, Australia
Nepean Hospital
Kingswood, New South Wales, Australia
St George Hospital
Kogarah, New South Wales, Australia
Liverpool Hospital
Liverpool, New South Wales, Australia
John Hunter Hospital
New Lambton Heights, New South Wales, Australia
Prince of Wales Hospital
Randwick, New South Wales, Australia
Royal North Shore Hospital
St Leonards, New South Wales, Australia
Wagga Wagga Base Hospital
Wagga Wagga, New South Wales, Australia
Westmead Hospital
Westmead, New South Wales, Australia
Wollongong Hospital
Wollongong, New South Wales, Australia
Royal Darwin Hospital
Tiwi, Northern Territory, Australia
The Prince Charles Hospital
Chermside, Queensland, Australia
Royal Brisbane and Women's Hospital
Herston, Queensland, Australia
Lyell McEwin Hospital
Elizabeth Vale, South Australia, Australia
Ballarat Health Services
Ballarat Central, Victoria, Australia
Eastern Health (Box Hill Hospital)
Box Hill, Victoria, Australia
Monash Health
Clayton, Victoria, Australia
Northern Health
Epping, Victoria, Australia
Alfred Hospital
Melbourne, Victoria, Australia
Royal Melbourne Hospital
Parkville, Victoria, Australia
Western Health
St Albans, Victoria, Australia
West Gippsland Hospital
Warragul, Victoria, Australia
Royal Perth Hospital
Perth, Western Australia, Australia
Steven Tong, Prof, Study Chair
Melbourne Health