Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial

University of Melbourne

Status and phase

Active, not recruiting

Phase 3

Conditions

SARS-CoV-2 Infection (COVID-19)

Treatments

Drug: (Arm Closed) Dalteparin

Drug: (Arm Closed) Enoxaparin

Biological: (Arm Never Opened) Hyperimmune globulin

Drug: (Arm Closed) Nafamostat Mesilate

Drug: Remdesivir

Drug: (Arm Closed) Tinzaparin

Drug: Nirmatrelvir-Ritonavir

Study type

Interventional

Funder types

Other

Identifiers

NCT04483960

X20-0159

Details and patient eligibility

About

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).

Full description

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

Enrollment

2,200 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

A.Core Platform (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.

B. Antiviral II Domain (all participants 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

Exclusion criteria

A. Core platform exclusions (all participants must not meet the following):

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
Patient is expected to be discharged from hospital today or tomorrow
More than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to proven SARS-CoV-2 infection
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):

Severe renal impairment, defined as eGFR<30ml/min or receipt of renal replacement therapy
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.
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
The patient is known to be pregnant or breastfeeding
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):

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:

No venous access is available and none can be created
Known hypersensitivity to remdesivir or its excipients

Will be excluded from receiving Nirmatrelvir/ritonavir if:

The patient is unable to take, tolerate or absorb oral or enteral medications
Known hypersensitivity to any of nirmatrelvir, ritonavir or its excipients
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:

The patient is in the Immune Suppressed Stratum
The patient is receiving or has received supplemental oxygen on the calendar day of eligibility assessment.
The patient is considered by the treating clinician to be at very high risk for progression to severe COVID-19

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Factorial Assignment

Masking

None (Open label)

2,200 participants in 11 patient groups

(Arm Closed) Antiviral - Standard of care

No Intervention group

Description:

Standard of care without nafamostat mesilate

(Arm Closed) Antiviral - nafamostat mesilate

Experimental group

Description:

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.

Treatment:

Drug: (Arm Closed) Nafamostat Mesilate

(Arm Closed) Anticoagulation - standard dose thromboprophylaxis

Active Comparator group

Description:

Patients will be administered a standard thromboprophylactic dose of low molecular weight heparin, choice of agent according to availability and local practice at the participating site.

Treatment:

Drug: (Arm Closed) Tinzaparin

Drug: (Arm Closed) Dalteparin

Drug: (Arm Closed) Enoxaparin

(Arm Closed) Anticoagulation - intermediate dose thromboprophylaxis

Experimental group

Description:

Patients will be administered an intermediate dose of low molecular weight heparin, choice of agent according to availability and local practice at the participating site. The maximum dose of enoxaparin will be 120 mg/d, tinzaparin 125 IU/kg/day (not available within Australia), and Dalteparin 15,000 IU/d.

Treatment:

Drug: (Arm Closed) Tinzaparin

Drug: (Arm Closed) Dalteparin

Drug: (Arm Closed) Enoxaparin

(Arm Closed) Anticoagulation - therapeutic anticoagulation

Experimental group

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

Treatment:

Drug: (Arm Closed) Tinzaparin

Drug: (Arm Closed) Dalteparin

Drug: (Arm Closed) Enoxaparin

(Arm Never Opened) Antibody - Standard of Care

No Intervention group

Description:

No hyperimmune globulin

(Arm Never Opened) Antibody - hyperimmune globulin

Experimental group

Description:

2 doses of 30mL (3x10mL vials) of COVID-19 Hyper-Immunoglobulin (Human) given over 2 days within 48 hours of randomisation

Treatment:

Biological: (Arm Never Opened) Hyperimmune globulin

Antiviral II - No antiviral agent

No Intervention group

Description:

Participants will receive no antiviral agents intended to be active against SARS-CoV-2 for 28 days or until hospital discharge, whichever occurs first.

Antiviral II - Nirmatrelvir-ritonavir

Experimental group

Description:

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

Treatment:

Drug: Nirmatrelvir-Ritonavir

Antiviral II - Remdisivir

Experimental group

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.

Treatment:

Drug: Remdesivir

Antiviral II - Nirmatrelvir-ritonavir + remdesivir

Experimental group

Description:

Participants will receive both nirmatrelvir-ritonavir and remdesivir using the dose and administration methods described above.

Treatment:

Drug: Remdesivir

Drug: Nirmatrelvir-Ritonavir