None listed
Conditions
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.
Interventions
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 in
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.
Sponsors
University of Melbourne
Study design
Allocation
Randomised controlled trial
Intervention model
Factorial
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Healthy volunteers
No
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
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
Outcome results
None listed