Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial
NCT ID: NCT04483960
Last Updated: 2024-05-16
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ACTIVE_NOT_RECRUITING
PHASE3
2200 participants
INTERVENTIONAL
2020-07-28
2025-12-31
Brief Summary
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Detailed Description
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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
Conditions
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Study Design
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RANDOMIZED
FACTORIAL
TREATMENT
NONE
Study Groups
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(Arm Closed) Antiviral - Standard of care
Standard of care without nafamostat mesilate
No interventions assigned to this group
(Arm Closed) Antiviral - 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.
(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.
(Arm Closed) Anticoagulation - standard dose thromboprophylaxis
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.
(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.
(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.
(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).
(Arm Closed) Anticoagulation - intermediate dose thromboprophylaxis
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.
(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.
(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.
(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).
(Arm Closed) Anticoagulation - therapeutic anticoagulation
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
(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.
(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.
(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).
(Arm Never Opened) Antibody - Standard of Care
No hyperimmune globulin
No interventions assigned to this group
(Arm Never Opened) Antibody - hyperimmune globulin
2 doses of 30mL (3x10mL vials) of COVID-19 Hyper-Immunoglobulin (Human) given over 2 days within 48 hours of randomisation
(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
Antiviral II - No antiviral agent
Participants will receive no antiviral agents intended to be active against SARS-CoV-2 for 28 days or until hospital discharge, whichever occurs first.
No interventions assigned to this group
Antiviral II - Nirmatrelvir-ritonavir
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.
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.
Antiviral II - Remdisivir
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.
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.
Antiviral II - Nirmatrelvir-ritonavir + remdesivir
Participants will receive both nirmatrelvir-ritonavir and remdesivir using the dose and administration methods described above.
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.
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.
Interventions
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(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.
(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.
(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.
(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).
(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
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.
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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
1\. Onset of COVID-related symptoms was more than 7 days (i.e., 168 hours) ago
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
18 Years
ALL
No
Sponsors
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The Peter Doherty Institute for Infection and Immunity
OTHER
Australasian Society for Infectious Diseases
OTHER
Hunter Medical Research Institute
UNKNOWN
Aotearoa Clinical Trials
UNKNOWN
Australian and New Zealand Intensive Care Research Centre
OTHER
University of Melbourne
OTHER
Responsible Party
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Associate Professor Steven Tong
Associate Professor
Principal Investigators
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Steven Tong, Prof
Role: STUDY_CHAIR
Melbourne Health
Locations
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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
Countries
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References
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Morpeth SC, Venkatesh B, Totterdell JA, McPhee GM, Mahar RK, Jones M, Bandara M, Barina LA, Basnet BK, Bowen AC, Burke AJ, Cochrane B, Denholm JT, Dhungana A, Dore GJ, Dotel R, Duffy E, Dummer J, Foo H, Gilbey TL, Hammond NE, Hudson BJ, Jha V, Jevaji PR, John O, Joshi R, Kang G, Kaur B, Kim S, Das SK, Lau JSY, Littleford R, Marsh JA, Marschner IC, Matthews G, Maze MJ, McArthur CJ, McFadyen JD, McMahon JH, McQuilten ZK, Molton J, Mora JM, Mudaliar V, Nguyen V, O'Sullivan MVN, Pant S, Park JE, Paterson DL, Price DJ, Raymond N, Rees MA, Robinson JO, Rogers BA, Ryu WS, Sasadeusz J, Shum O, Snelling TL, Sommerville C, Trask N, Lewin SR, Hills TE, Davis JS, Roberts JA, Tong SYC. A Randomized Trial of Nafamostat for Covid-19. NEJM Evid. 2023 Nov;2(11):EVIDoa2300132. doi: 10.1056/EVIDoa2300132. Epub 2023 Oct 18.
McQuilten ZK, Venkatesh B, Jha V, Roberts J, Morpeth SC, Totterdell JA, McPhee GM, Abraham J, Bam N, Bandara M, Bangi AK, Barina LA, Basnet BK, Bhally H, Bhusal KR, Bogati U, Bowen AC, Burke AJ, Christopher DJ, Chunilal SD, Cochrane B, Curnow JL, Das SK, Dhungana A, Di Tanna GL, Dotel R, DSouza H, Dummer J, Dutta S, Foo H, Gilbey TL, Giles ML, Goli K, Gordon A, Gyanwali P, Haksar D, Hudson BJ, Jani MK, Jevaji PR, Jhawar S, Jindal A, John MJ, John M, John FB, John O, Jones M, Joshi RD, Kamath P, Kang G, Karki AR, Karmalkar AM, Kaur B, Koganti KC, Koshy JM, Krishnamurthy MS, Lau JS, Lewin SR, Lim LL, Marschner IC, Marsh JA, Maze MJ, McGree JM, McMahon JH, Medcalf RL, Merriman EG, Misal AP, Mora JM, Mudaliar VK, Nguyen V, O'Sullivan MV, Pant S, Pant P, Paterson DL, Price DJ, Rees MA, Robinson JO, Rogers BA, Samuel S, Sasadeusz J, Sharma D, Sharma PK, Shrestha R, Shrestha SK, Shrestha P, Shukla U, Shum O, Sommerville C, Spelman T, Sullivan RP, Thatavarthi U, Tran HA, Trask N, Whitehead CL, Mahar RK, Hammond NE, McFadyen JD, Snelling TL, Davis JS, Denholm JT, Tong SYC. Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19. NEJM Evid. 2023 Feb;2(2):EVIDoa2200293. doi: 10.1056/EVIDoa2200293. Epub 2022 Dec 10.
Denholm JT, Venkatesh B, Davis J, Bowen AC, Hammond NE, Jha V, McPhee G, McQuilten Z, O'Sullivan MVN, Paterson D, Price D, Rees M, Roberts J, Jones M, Totterdell J, Snelling T, Trask N, Morpeth S, Tong SY; ASCOT ADAPT investigators. ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial. Trials. 2022 Dec 14;23(1):1014. doi: 10.1186/s13063-022-06929-y.
Bassi A, Arfin S, Joshi R, Bathla N, Hammond NE, Rajbhandari D, Tirupakuzhi Vijayaraghavan BK, Venkatesh B, Jha V. Challenges in operationalising clinical trials in India during the COVID-19 pandemic. Lancet Glob Health. 2022 Mar;10(3):e317-e319. doi: 10.1016/S2214-109X(21)00546-5. Epub 2021 Dec 22. No abstract available.
Other Identifiers
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X20-0159
Identifier Type: -
Identifier Source: org_study_id
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