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Trial registered on ANZCTR


Registration number
ACTRN12620000445976
Ethics application status
Approved
Date submitted
2/04/2020
Date registered
6/04/2020
Date last updated
21/05/2024
Date data sharing statement initially provided
6/04/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Australasian COVID-19 Trial (ASCOT): A multi-centre randomised adaptive platform clinical trial to assess clinical, virological and immunological outcomes in patients with SARS-CoV-2 infection (COVID-19)
Scientific title
Australasian COVID-19 Trial (ASCOT): An International Multi-Centre Randomised Adaptive Platform Clinical Trial to Assess Different Treatment Regimens on the Clinical, Virological and Immunological Outcomes in Patients Diagnosed with SARS-CoV-2 Infection (COVID-19).
Secondary ID [1] 300905 0
NCT04483960.
Universal Trial Number (UTN)
U1111-1250-5165
Trial acronym
ASCOT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 (SARS-CoV-2) 316847 0
Condition category
Condition code
Infection 315075 315075 0 0
Other infectious diseases
Respiratory 315105 315105 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatments in ASCOT ADAPT are divided into different intervention domains. Depending on eligibility and availability of the invention at participating sites, participants are randomised to receive one intervention from each domain, and therefore, can receive a combination of treatments.

(Domain Closed) Domain A - Antiviral Interventions:
Intervention 1A
Intervention Type: Drug
Intervention Administration: Intravenous infusion
Intervention Name: Nafamostat
Intervention Description: Continuous infusion of nafamostat (0.2mg/kg/hr) for 7 days or until hospital discharge (whichever is earlier).
Intervention Adherence: direct supervision while in hospital.

Intervention 2A
Intervention Type: Other
Intervention Administration: Various
Intervention Name: Standard of care
Intervention Description: Routine usual medical care given by medical doctors to treat and control symptoms (i.e. medications for pain or oxygen therapy) of COVID-19.
Intervention Adherence: direct supervision while in hospital.

(Domain Never Opened) Domain B - Therapeutic Antibody Interventions:
Intervention 1B
Intervention Type: Biological
Intervention Administration: Intravenous infusion
Intervention Name: Hyperimmune globulin
Intervention Description: 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.
Intervention Adherence: direct supervision while in hospital.

Intervention 2B
Intervention Type: Other
Intervention Administration: Various
Intervention Name: Standard of care
Intervention Description: Routine usual medical care without antibody therapies, given by medical doctors to treat and control symptoms (i.e. medications for pain or oxygen therapy) of COVID-19.
Intervention Adherence: direct supervision while in hospital.

(Domain Closed) Domain C - Anticoagulation Interventions:
Intervention 1C
Intervention Type: Drug
Intervention Administration: Injection
Intervention Name: Standard dose thromboprophylaxis.
Intervention Description: Standard dose of low molecular weight heparin (LMWH) daily until hospital discharge, admission to intensive care unit (ICU) or for a maximum of 28 days from randomisation. Choice of LMWH according to availability and local practice at the participating site, including Enoxaparin (dose 20mg if <50kg, 40mg if 50-120kg, 60mg if >120kg q24h), Tinzaparin (dose 75IU/kg q24h) or Dalteparin (dose 2500IU if <40kg, 5000IU if 40-120kg, 7500IU if >120kg q24h)
Intervention Adherence: direct supervision while in hospital.

Intervention 2C
Intervention Type: Drug
Intervention Administration: Injection
Intervention Name: Intermediate dose thromboprophylaxis.
Intervention Description: Intermediate dose of LMWH daily until hospital discharge, admission to ICU or for a maximum of 28 days from randomisation. Choice of LMWH according to availability and local practice at the participating site, including Enoxaparin (dose 40mg q24h if <50kg, 40mg q12h or 80mg q24h if 50-120kg, 60mg q12h or 120mg q24h if >120kg), Tinzaparin (dose 125IU/kg/day) or Dalteparin (dose 5000IU q24h if <40kg, 5000IU q12h or 10,000IU q24h if 40-120kg, 7500IU q12h or 15,000IU q24h if >120kg)
Intervention Adherence: direct supervision while in hospital.

Intervention 3C
Intervention Type: Drug
Intervention Administration: Injection
Intervention Name: Therapeutic anticoagulation
Intervention Description: Therapeutic anticoagulation administered with LMWH daily until hospital discharge, admission to ICU or for a maximum of 28 days from randomisation. Choice of LMWH according to availability and local practice at the participating site, including Enoxaparin (dose 1mg/kg q12h or 1.5mg/kg q24h), Tinzaparin (dose 175IU/kg q24h) or Dalteparin (dose 100IU/kg q12h or 200IU/kg q24h)
Intervention Adherence: direct supervision while in hospital.

Domain Q - COVID-19 Antiviral II Domain
Intervention 1Q
Intervention Type: Other
Intervention Administration: Other
Intervention Name: No antiviral agent
Intervention Description: Patients assigned to this intervention are not to receive antiviral agents intended to be active against SARS-CoV-2 for 28 days or until hospital discharge, whichever occurs first.
Intervention Adherence: direct supervision while in hospital.

Intervention 2Q
Intervention Type: Drug
Intervention Administration: Oral/enteral
Intervention Name: Nirmatrelvir-ritonavir
Intervention Description: 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.
Intervention Adherence: direct supervision while in hospital.

Intervention 3Q
Intervention Type: Drug
Intervention Administration: Intravenous infusion
Intervention Name: Remdesivir
Intervention Description: 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
Intervention Adherence: direct supervision while in hospital.

Intervention 4Q
Intervention Type: Drug
Intervention Administration: Intravenous infusion and oral/enteral
Intervention Name: Nirmatrelvir-ritonavir + remdesivir
Intervention Description: The drug dosing and administration for participants receiving oral nirmatrelvir-ritonavir + intravenous remdesivir is the same as outlined in 2Q and 3Q above.
Intervention Adherence: direct supervision while in hospital.
Intervention code [1] 317227 0
Treatment: Drugs
Intervention code [2] 319059 0
Treatment: Other
Comparator / control treatment
Treatment contrasts will be:
-Superiority: Intervention is better than alternative interventions within a domain for that strata group.
-Inferiority: Intervention is worse than alternative interventions within a domain for that strata group.
-Equivalence: Intervention is not better or worse (i.e. it is equivalent) to at least one other alternative intervention within a domain for that strata group
Control group
Active

Outcomes
Primary outcome [1] 323371 0
A hierarchical ordinal scale that is a composite of mortality during the acute hospital
admission and the duration of organ failure support while admitted to an ICU up until the end of study day 21. Death and duration of organ support collected from patient medical records.
Timepoint [1] 323371 0
End of study day 21 after randomisation
Secondary outcome [1] 381687 0
Core Secondary Outcome:
Modified WHO ordinal outcome scale at day 14 after randomisation
The modified ordinal score is:
1. Not hospitalised
2. Hospitalised
3. Hospitalised, requiring supplemental oxygen
4. Hospitalised, on non-invasive ventilation or high flow oxygen devices
5. Hospitalised, on invasive mechanical ventilation or ECMO
6. Death.
Note. Admission to a Hospital in the Home unit is not counted as hospitalisation for the purposes of this ordinal scale. Patients who have been admitted to hospital and transferred to a Hospital in the Home unit will be assessed as either ordinal score 1 or 2.
Data collected from patient medical records.
Timepoint [1] 381687 0
14 days after randomisation
Secondary outcome [2] 381688 0
Core secondary outcome:

All-cause mortality
Timepoint [2] 381688 0
28, 90 and 180 days after randomisation
Secondary outcome [3] 381690 0
Core Secondary Outcomes:
Days alive and free of hospital, as it applies to the index hospital admission, by 28 days after randomisation

Note 1. Days spent in a Hospital in the Home unit will not be counted as days in hospital as hospital means ‘acute-care hospital’ for the purposes of this endpoint.

Note 2. If patient is discharged prior to day 28, it will be assumed the patient has not been readmitted to hospital.
Timepoint [3] 381690 0
By 28 days after randomisation
Secondary outcome [4] 381725 0
Core Secondary Outcome:
Days alive and free of supplemental oxygen, invasive or non-invasive ventilation by 28 days after randomisation
Note. If patient is discharged prior to day 28, it will be assumed that they have not received any supplemental oxygen, invasive or non-invasive ventilation since discharge.
Timepoint [4] 381725 0
By 28 days after randomisation
Secondary outcome [5] 381749 0
[No longer collected. Domain closed] Antiviral domain-specific secondary outcome: Viral clearance. Proportion of patients with negative SARS-CoV-2 RT-PCR at day 3 (post randomisation) and day 7 from upper or lower respiratory tract samples, for those with results available.
Timepoint [5] 381749 0
Day 3 and day 7 post randomisation
Secondary outcome [6] 388871 0
[No longer collected. Domain never opened]. Antibody domain-specific secondary outcome: Confirmed arterial thrombosis (acute myocardial infarction, ischemic cerebrovascular event, other) as assessed by patient medical records.
Timepoint [6] 388871 0
Up to day 28
Secondary outcome [7] 391446 0
[No longer collected. Domain never opened]. Antibody domain-specific secondary outcome: Haemolysis - defined as fever and other symptoms/signs of haemolysis confirmed by one or more of the following: • Fall of haemoglobin • Rise in lactic dehydrogenase • Rise in bilirubin • Positive direct antiglobulin test • Positive crossmatch Haemolysis within 72 hours Assessed using patient medical records.
Timepoint [7] 391446 0
Within 72 hours of last transfusion
Secondary outcome [8] 391447 0
[No longer collected. Domain never opened]. Antibody domain-specific secondary outcome: Occurrence of any of the following serious treatment-related adverse events (assessed via medical records): 1) Serious allergic reaction or anaphylaxis; 2) Transfusion-related acute lung injury (TRALI)
Timepoint [8] 391447 0
Within 24 hours of intervention administration
Secondary outcome [9] 391448 0
[No longer collected. Domain closed]. Antiviral domain-specific secondary outcome: Viral load. Changes in cycle threshold value in RT-PCR for SARS-CoV-2 from baseline to day 3 and from baseline to day 7, for those with results available from the same respiratory tract sample type.
Timepoint [9] 391448 0
Baseline and Day 3 and day 7 post randomisation
Secondary outcome [10] 391449 0
[No longer collected. Domain closed]. Antiviral domain-specific secondary outcome: Safety: Elevation of Alanine Transaminase (ALT) or Aspartate Transaminase (AST) to >5x upper limit of normal assessed via medical records
Timepoint [10] 391449 0
At any time while admitted to hospital (censored at day of discharge)
Secondary outcome [11] 391450 0
[No longer collected. Domain closed]. Anticoagulation domain-specific secondary outcome: Confirmed deep venous thrombosis, assessed via medical records.
Timepoint [11] 391450 0
Up to day 28 post randomisation
Secondary outcome [12] 391451 0
[No longer collected. Domain closed]. Anticoagulation domain-specific secondary outcome: Other confirmed thrombotic event up to 28 days after randomisation.
Timepoint [12] 391451 0
During index hospitalisation, up to day 28 post randomisation.
Secondary outcome [13] 391452 0
[No longer collected] Core secondary outcome: Time to clinical recovery. Time to clinical recovery is defined as the first day, during the 28 days after enrolment, on which a patient satisfies categories 1, 2, or 3 on the WHO eight-point ordinal outcome scale. For the purposes of this outcome measure, it will be assumed that the participant is not hospitalised on the first day following discharge.
Timepoint [13] 391452 0
up to 28 days after randomisation
Secondary outcome [14] 391453 0
Core secondary outcome:

Presence of patient-reported outcome of shortness of breath.

1. Dichotomous comparison of a subjective measure of shortness of breath such as: “Are you currently experiencing shortness of breath that you didn’t have before you got COVID, or which is worse now than before you got COVID?”

2. Ordinal comparison of the modified Medical Research Council (mMRC) breathlessness scale:
0=I only get breathless with strenuous exercise;
1=I get short of breath when hurrying on level ground or walking up a slight hill;
2=On level ground, I walk slower than people of the same age because of breathlessness, or I have to stop for breath when walking at my own pace on the level;
3=I stop for breath after walking about 100 metres or after a few minutes on level ground;
4=I am too breathless to leave the house or I am breathless when dressing or undressing
Timepoint [14] 391453 0
180 days after randomisation.
Secondary outcome [15] 391454 0
Core secondary outcome:

Quality of life as measured by EQ-5D-5L questionnaire
Timepoint [15] 391454 0
180 days after randomisation
Secondary outcome [16] 391455 0
[No longer collected. Domain never opened]. Antibody domain-specific secondary outcome: Confirmed venous thrombosis (deep vein thrombosis, pulmonary embolus, other) as assessed by patient medical records.
Timepoint [16] 391455 0
Up to day 28
Secondary outcome [17] 391456 0
[No longer collected. Domain closed]. Antiviral domain-specific secondary outcome: Safety: Elevation of serum potassium to >5.5 mmol/L (assessed via medical records)
Timepoint [17] 391456 0
While admitted to hospital (censored at day of discharge).
Secondary outcome [18] 391457 0
[No longer collected. Domain closed]. Antiviral domain-specific secondary outcome: Safety: Decrease of serum sodium to <125 mmol/L (assessed via medical records)
Timepoint [18] 391457 0
While admitted to hospital (censored at day of discharge)
Secondary outcome [19] 391458 0
[No longer collected. Domain closed]. Antiviral domain-specific secondary outcome: Safety: Major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH; assessed via medical records)
Timepoint [19] 391458 0
While admitted to hospital (censored on day of discharge)
Secondary outcome [20] 391459 0
[No longer collected. Domain closed]. Antiviral domain-specific secondary outcome: Safety: Thrombophlebitis/vasculitis at IV line site (assessed via medical records).
Timepoint [20] 391459 0
While admitted to hospital (censored on day of discharge)
Secondary outcome [21] 391460 0
[No longer collected. Domain closed]. Anticoagulation domain-specific secondary outcome: Confirmed pulmonary embolus assessed via medical records.
Timepoint [21] 391460 0
Up to 28 days after randomisation
Secondary outcome [22] 391461 0
[No longer collected. Domain closed]. Anticoagulation domain-specific secondary outcome: Confirmed acute myocardial infarction assessed via medical records.
Timepoint [22] 391461 0
Up to 28 days after randomisation.
Secondary outcome [23] 391462 0
[No longer collected. Domain closed]. Anticoagulation domain-specific secondary outcome: Confirmed ischemic cerebrovascular event assessed via medical records.
Timepoint [23] 391462 0
Up to 28 days after randomisation
Secondary outcome [24] 391463 0
[No longer collected. Domain closed]. Anticoagulation domain-specific secondary outcome: Confirmed deep vein thrombosis assessed via medical records.
Timepoint [24] 391463 0
Up to 28 days after randomisation
Secondary outcome [25] 391464 0
[No longer collected. Domain closed]. Anticoagulation domain-specific secondary outcome: Major bleeding (as defined by ISTH) assessed via medical records.
Timepoint [25] 391464 0
Up to 28 days after randomisation
Secondary outcome [26] 391465 0
[No longer collected. Domain closed]. Anticoagulation domain-specific secondary outcome: Clinically relevant non-major bleeding (as defined by ISTH) assessed via medical records.
Timepoint [26] 391465 0
Up to 28 days after randomisation.
Secondary outcome [27] 391466 0
[No longer collected. Domain closed]. Anticoagulation domain-specific secondary outcome: Heparin-induced thrombocytopenia during index hospitalisation, assessed via medical records
Timepoint [27] 391466 0
Up to 28 days after randomisation
Secondary outcome [28] 401804 0
[No longer collected. Domain closed]. Antiviral domain-specific secondary outcome: Safety: Clinically relevant non-major bleeding (as defined by ISTH) assessed via medical records.
Timepoint [28] 401804 0
While admitted to hospital (censored on day of discharge)
Secondary outcome [29] 435325 0
Core Secondary Outcome:
Days alive and free of invasive or non-invasive ventilation or high flow oxygen by 28 days after randomisation. Collected from patient medical records.

Note. If patient is discharged prior to day 28, it will be assumed that they have not received any invasive or non-invasive ventilation since discharge.
Timepoint [29] 435325 0
Secondary outcome [30] 435326 0
Core Secondary Outcome:
Days alive and free of invasive or non-invasive ventilation or high flow oxygen by 28 days after randomisation. Collected from patient medical records.

Note. If patient is discharged prior to day 28, it will be assumed that they have not received any invasive or non-invasive ventilation since discharge.
Timepoint [30] 435326 0
28 days after randomisation
Secondary outcome [31] 435327 0
Core Secondary Outcome:
Days alive and free of invasive mechanical ventilation by 28 days after randomisation

Note. If patient is discharged prior to day 28, it will be assumed that they have not received any invasive ventilation since discharge.

Data collected from patient medical records.
Timepoint [31] 435327 0
28 days after randomisation
Secondary outcome [32] 435328 0
Core Secondary Outcome:
Days alive and free of invasive mechanical ventilation by 28 days after randomisation

Note. If patient is discharged prior to day 28, it will be assumed that they have not received any invasive ventilation since discharge.

Data collected from patient medical records.
Timepoint [32] 435328 0
28 days after randomisation
Secondary outcome [33] 435329 0
Core Secondary Outcome:
Destination at time of hospital discharge (characterised as home, rehabilitation hospital, nursing home, or long-term care facility, or another acute hospital)
Data collected from patient medical record
Timepoint [33] 435329 0
28 days after randomisation
Secondary outcome [34] 435330 0
Core Secondary Outcome:
Destination at time of hospital discharge (characterised as home, rehabilitation hospital, nursing home, or long-term care facility, or another acute hospital)
Data collected from patient medical record
Timepoint [34] 435330 0
Discharge
Secondary outcome [35] 435331 0
Core Secondary Outcome: Admission (or re-admission) to ICU during the index hospitalisation, censored at 90 days post-randomisation. Data collected from patient medical records.
Timepoint [35] 435331 0
Discharge
Secondary outcome [36] 435332 0
Core Secondary Outcome: Admission (or re-admission) to ICU during the index hospitalisation, censored at 90 days post-randomisation. Data collected from patient medical records.
Timepoint [36] 435332 0
During the participant's index hospitalisation. Censored 90 days after randomisation.
Secondary outcome [37] 435333 0
Core secondary outcome measures for participants admitted to ICU: ICU mortality, censored at 90 days post-randomisation. Data collected from patient medical records.
Timepoint [37] 435333 0
During the participant's index hospitalisation. Censored 90 days after randomisation.
Secondary outcome [38] 435334 0
Core secondary outcome measures for participants admitted to ICU: ICU mortality, censored at 90 days post-randomisation. Data collected from patient medical records.
Timepoint [38] 435334 0
Up to 90 days after randomisation.
Secondary outcome [39] 435335 0
Core secondary outcome measures for participants admitted to ICU:
ICU length of stay, censored at 90 days post-randomisation. Data collected from patient medical records.
Timepoint [39] 435335 0
Up to 90 days after randomisation.
Secondary outcome [40] 435336 0
Core secondary outcome measures for participants admitted to ICU:
ICU length of stay, censored at 90 days post-randomisation. Data collected from patient medical records.
Timepoint [40] 435336 0
Up to 90 days after randomisation
Secondary outcome [41] 435337 0
Core secondary outcome measures for participants admitted to ICU:
Ventilator-free days, censored at 28 days post-randomisation. Data collected from patient medical records.
Timepoint [41] 435337 0
Up to 90 days after randomisation
Secondary outcome [42] 435338 0
Core secondary outcome measures for participants admitted to ICU:
Ventilator-free days, censored at 28 days post-randomisation. Data collected from patient medical records.
Timepoint [42] 435338 0
Up to 28 days after randomisation
Secondary outcome [43] 435339 0
Core secondary outcome measures for participants admitted to ICU:
Organ failure free days. Data collected from patient medical records.
Timepoint [43] 435339 0
Up to 28 days after randomisation
Secondary outcome [44] 435340 0
Core secondary outcome measures for participants admitted to ICU:
Organ failure free days. Data collected from patient medical records.
Timepoint [44] 435340 0
Up to 28 days after randomisation
Secondary outcome [45] 435341 0
Antiviral II Domain Secondary Outcome:
Length of hospital stay (in days). Data collected from patient medical record.
Timepoint [45] 435341 0
Up to 28 days after randomisation
Secondary outcome [46] 435342 0
Antiviral II Domain Secondary Outcome:
Length of hospital stay (in days). Data collected from patient medical record.
Timepoint [46] 435342 0
During the participant's index hospitalisation. Censored 90 days after enrolment.
Secondary outcome [47] 435343 0
Antiviral II Domain Secondary Outcome:
Proportion of participants with baseline respiratory symptoms in whom all acute respiratory symptoms have resolved at study day 7 after randomisation. Data collected from patient medical records or directly from the patient or proxy.

Note 1. Respiratory symptoms are defined as one or more of: cough, sore throat, runny nose sneezing, shortness of breath or chest pain. “Acute” means the symptom in question is not usually present in that individual, or during the current COVID episode was substantially worse or more frequent than usual.
Note 2. Resolution of all acute respiratory symptoms means return to baseline state – not necessarily the absence of all respiratory symptoms.
Note 3. Ongoing non-respiratory symptoms (such as fatigue, anorexia, delirium, diarrhea) are not counted as part of this endpoint.
Timepoint [47] 435343 0
During the participant's index hospitalisation. Censored 90 days after enrolment.
Secondary outcome [48] 435344 0
Antiviral II Domain Secondary Outcome:
Proportion of participants with baseline respiratory symptoms in whom all acute respiratory symptoms have resolved at study day 7 after randomisation. Data collected from patient medical records or directly from the patient or proxy.

Note 1. Respiratory symptoms are defined as one or more of: cough, sore throat, runny nose sneezing, shortness of breath or chest pain. “Acute” means the symptom in question is not usually present in that individual, or during the current COVID episode was substantially worse or more frequent than usual.
Note 2. Resolution of all acute respiratory symptoms means return to baseline state – not necessarily the absence of all respiratory symptoms.
Note 3. Ongoing non-respiratory symptoms (such as fatigue, anorexia, delirium, diarrhea) are not counted as part of this endpoint.
Timepoint [48] 435344 0
7 days after randomisation

Eligibility
Key inclusion criteria
Core Platform Inclusion Criteria (all participants must meet the following):
Adult (as defined by local jurisdiction) patient admitted to hospital with acute illness and suspected or proven SARS-CoV-2 infection.

Antiviral II Inclusion Criteria (all patients at sites participating in the Antiviral II Domain must meet the following) :
SARS-CoV-2 infection has been confirmed by positive rapid antigen test OR polymerase chain reaction test within the last 7 days
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
A. Core Platform Exclusion Criteria (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 Exclusion Criteria (all 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


Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants may be randomised using response adaptive randomisation (RAR), that is the ratio of randomisation to each regimen will be proportional to the posterior probability that it is the optimal regimen for that participant, depending on their State and Strata membership. At commencement, initial randomisation ratios will be equal across all regimens; in other words, no assumptions will be made about the relative efficacy of each intervention prior to the first examination of the accumulating data.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Regular adaptive analyses will be undertaken using a Bayesian Hierarchical Model that can estimate the probability of superiority, efficacy, inferiority, equivalence, non-inferiority, harm or futility relative to pre-defined reference levels.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 16270 0
Blacktown Hospital - Blacktown
Recruitment hospital [2] 16272 0
John Hunter Hospital - New Lambton
Recruitment hospital [3] 16274 0
Liverpool Hospital - Liverpool
Recruitment hospital [4] 16276 0
Nepean Hospital - Kingswood
Recruitment hospital [5] 16279 0
Prince of Wales Hospital - Randwick
Recruitment hospital [6] 16281 0
St George Hospital - Kogarah
Recruitment hospital [7] 16285 0
Wollongong Hospital - Wollongong
Recruitment hospital [8] 16286 0
Westmead Hospital - Westmead
Recruitment hospital [9] 16296 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [10] 16298 0
The Prince Charles Hospital - Chermside
Recruitment hospital [11] 16301 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [12] 16311 0
Royal Perth Hospital - Perth
Recruitment hospital [13] 16327 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment hospital [14] 16328 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [15] 16329 0
Dandenong Hospital - Dandenong
Recruitment hospital [16] 16330 0
Casey Hospital - Berwick
Recruitment hospital [17] 16331 0
The Northern Hospital - Epping
Recruitment hospital [18] 16338 0
Footscray Hospital - Footscray
Recruitment hospital [19] 16339 0
Sunshine Hospital - St Albans
Recruitment hospital [20] 18005 0
Ballarat Health Services (Base Hospital) - Ballarat Central
Recruitment hospital [21] 18008 0
Campbelltown Hospital - Campbelltown
Recruitment hospital [22] 18011 0
Wagga Wagga Base Hospital - Wagga Wagga
Recruitment hospital [23] 18013 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [24] 26562 0
Royal Darwin Hospital - Tiwi
Recruitment postcode(s) [1] 42604 0
0810 - Tiwi
Recruitment postcode(s) [2] 29824 0
2031 - Randwick
Recruitment postcode(s) [3] 31982 0
2065 - St Leonards
Recruitment postcode(s) [4] 29831 0
2145 - Westmead
Recruitment postcode(s) [5] 29815 0
2148 - Blacktown
Recruitment postcode(s) [6] 29819 0
2170 - Liverpool
Recruitment postcode(s) [7] 29826 0
2217 - Kogarah
Recruitment postcode(s) [8] 29817 0
2305 - New Lambton
Recruitment postcode(s) [9] 29830 0
2500 - Wollongong
Recruitment postcode(s) [10] 31977 0
2560 - Campbelltown
Recruitment postcode(s) [11] 31980 0
2650 - Wagga Wagga
Recruitment postcode(s) [12] 29821 0
2747 - Kingswood
Recruitment postcode(s) [13] 29882 0
3011 - Footscray
Recruitment postcode(s) [14] 29883 0
3021 - St Albans
Recruitment postcode(s) [15] 29872 0
3052 - Parkville
Recruitment postcode(s) [16] 29876 0
3076 - Epping
Recruitment postcode(s) [17] 29873 0
3168 - Clayton
Recruitment postcode(s) [18] 29874 0
3175 - Dandenong
Recruitment postcode(s) [19] 31974 0
3350 - Ballarat Central
Recruitment postcode(s) [20] 29875 0
3806 - Berwick
Recruitment postcode(s) [21] 29841 0
4029 - Herston
Recruitment postcode(s) [22] 29843 0
4032 - Chermside
Recruitment postcode(s) [23] 29846 0
5112 - Elizabeth Vale
Recruitment postcode(s) [24] 29856 0
6000 - Perth
Recruitment outside Australia
Country [1] 22462 0
New Zealand
State/province [1] 22462 0

Funding & Sponsors
Funding source category [1] 305377 0
University
Name [1] 305377 0
University of Melbourne
Country [1] 305377 0
Australia
Funding source category [2] 305393 0
University
Name [2] 305393 0
University of Queensland
Country [2] 305393 0
Australia
Funding source category [3] 305394 0
Other
Name [3] 305394 0
Hunter Medical Research Institute: a partnership between the University of Newcastle, Hunter New England Local Health District
Country [3] 305394 0
Australia
Funding source category [4] 305395 0
Charities/Societies/Foundations
Name [4] 305395 0
The Pratt Foundation
Country [4] 305395 0
Australia
Funding source category [5] 305396 0
Charities/Societies/Foundations
Name [5] 305396 0
Royal Brisbane Women's Hospital Foundation
Country [5] 305396 0
Australia
Funding source category [6] 305397 0
Charities/Societies/Foundations
Name [6] 305397 0
Hospital Research Foundation
Country [6] 305397 0
Australia
Funding source category [7] 307201 0
Charities/Societies/Foundations
Name [7] 307201 0
The Minderoo Foundation
Country [7] 307201 0
Australia
Funding source category [8] 307202 0
Commercial sector/Industry
Name [8] 307202 0
BHP
Country [8] 307202 0
Australia
Funding source category [9] 307203 0
Other
Name [9] 307203 0
New Zealand Health Research Council
Country [9] 307203 0
New Zealand
Funding source category [10] 307204 0
Charities/Societies/Foundations
Name [10] 307204 0
Macquarie Group Foundation
Country [10] 307204 0
Australia
Funding source category [11] 307205 0
Government body
Name [11] 307205 0
Medical Research Future Fund
Country [11] 307205 0
Australia
Funding source category [12] 316565 0
Government body
Name [12] 316565 0
NSW Office for Health and Medical Research (OHMR)
Country [12] 316565 0
Australia
Funding source category [13] 316566 0
Government body
Name [13] 316566 0
Victorian State Government
Country [13] 316566 0
Australia
Primary sponsor type
University
Name
University of Melbourne
Address
Parkville, VIC, 3050
Country
Australia
Secondary sponsor category [1] 305775 0
Other
Name [1] 305775 0
Aotearoa Clinical Trials
Address [1] 305775 0
Aotearoa Clinical Trials, Private Bag 93311, Otahuhu 1640 Auckland, New Zealand
Country [1] 305775 0
New Zealand
Secondary sponsor category [2] 307807 0
Other
Name [2] 307807 0
The George Institute for Global Health
Address [2] 307807 0
Level 5, 1 King Street
Newtown 2042
NSW, Australia
Country [2] 307807 0
Australia
Other collaborator category [1] 281261 0
Other Collaborative groups
Name [1] 281261 0
The Australasian Society for Infectious Diseases Clinical Research Network (ASID CRN)
Address [1] 281261 0
Suite 302, Level 3, 478 George Street
Sydney NSW 2000
Australia
Country [1] 281261 0
Australia
Other collaborator category [2] 283044 0
Other Collaborative groups
Name [2] 283044 0
Hunter Medical Research Institute (HMRI)
Address [2] 283044 0
Country [2] 283044 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305686 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 305686 0
Royal Melbourne Hospital Office for Research
CITY CAMPUS
Level 2
South West
300 Grattan Street
Parkville Victoria 3050
Ethics committee country [1] 305686 0
Australia
Date submitted for ethics approval [1] 305686 0
20/03/2020
Approval date [1] 305686 0
03/04/2020
Ethics approval number [1] 305686 0
HREC/62646/MH-2020
Ethics committee name [2] 315353 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [2] 315353 0
https://www.slhd.nsw.gov.au/rpa/research/
Ethics committee country [2] 315353 0
Australia
Date submitted for ethics approval [2] 315353 0
18/07/2023
Approval date [2] 315353 0
15/08/2023
Ethics approval number [2] 315353 0
2023/ETH01712

Summary
Brief summary
ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled Bayesian adaptive platform trial. The aim of the trial is to identify the best regimen (combination of interventions) to treat adults hospitalised with COVID-19.
Trial website
https://www.ascot-trial.edu.au/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101226 0
A/Prof Steven Tong
Address 101226 0
The Peter Doherty Institute for Infection and Immunity
792 Elizabeth Street
Melbourne, Victoria 3000
Country 101226 0
Australia
Phone 101226 0
+61 03 9342 9406
Fax 101226 0
Email 101226 0
steven.tong@unimelb.edu.au
Contact person for public queries
Name 101227 0
A/Prof Steven Tong
Address 101227 0
The Peter Doherty Institute for Infection and Immunity
792 Elizabeth Street
Melbourne, Victoria 3000
Country 101227 0
Australia
Phone 101227 0
+61 03 9342 9406
Fax 101227 0
Email 101227 0
ascot-team@unimelb.edu.au
Contact person for scientific queries
Name 101228 0
A/Prof Steven Tong
Address 101228 0
The Peter Doherty Institute for Infection and Immunity
792 Elizabeth Street
Melbourne, Victoria 3000
Country 101228 0
Australia
Phone 101228 0
+61 03 9342 9406
Fax 101228 0
Email 101228 0
steven.tong@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The trial steering committee will be the custodians of the final trial dataset. No-one outside the trial steering committee will be given access to the data without the permission of the trial steering committee. No identifying data will be given to any third parties at any stage.


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseNafamostat Mesylate for Treatment of COVID-19 in Hospitalised Patients: A Structured, Narrative Review.2022https://dx.doi.org/10.1007/s40262-022-01170-x
EmbaseEfficacy and safety outcomes of proposed randomized controlled trials investigating hydroxychloroquine and chloroquine during the early stages of the COVID-19 pandemic.2021https://dx.doi.org/10.1111/bcp.14598
EmbaseClinical trials for the prevention and treatment of COVID-19: current state of play.2020https://dx.doi.org/10.5694/mja2.50673
EmbaseASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial.2022https://dx.doi.org/10.1186/s13063-022-06929-y
EmbaseThe Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial.2020https://dx.doi.org/10.1186/s13063-020-04576-9