Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial

NCT04483960 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: X20-0159
• Study Type: interventional
• Target: 2,200
• Locations: 1 country
• Sites: 25

Brief Summary

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).

Conditions

SARS-CoV-2 Infection (COVID-19)

Outcome Measures

Primary Outcomes (1)

• 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.

  * All patients who die before discharge from an acute hospital, irrespective of whether this occurs before or after day 21, will be coded as -1. * Survivors who receive organ failure support while admitted to an ICU within 21 days are assigned a score from 0 to 21 calculated as whole or part study days for which the patient is alive and not receiving organ failure support while admitted to an ICU up until the end of study day 21. * Survivors who never receive organ failure support while admitted to an ICU before the end of study day 21 will be coded as 22.

  Day 21

Secondary Outcomes (16)

• Core Secondary Outcome: WHO 8-point ordinal outcome scale

  Day 14

• Core Secondary Outcome: All-cause mortality

  Day 28, 90 and 180

• Core Secondary Outcome: Days alive and free of hospital

  Day 28

• Core Secondary Outcome: Days alive and free of supplemental oxygen, invasive or non-invasive ventilation

  Day 28

• Core Secondary Outcome: Days alive and free of invasive or non-invasive ventilation or high flow oxygen

  Day 28

Study Arms (11)

(Arm Closed) Antiviral - Standard of care

NO INTERVENTION

Standard of care without nafamostat mesilate

(Arm Closed) Antiviral - nafamostat mesilate

EXPERIMENTAL

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.

Drug: (Arm Closed) Nafamostat Mesilate

(Arm Closed) Anticoagulation - standard dose thromboprophylaxis

ACTIVE COMPARATOR

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.

Drug: (Arm Closed) Enoxaparin; Drug: (Arm Closed) Dalteparin; Drug: (Arm Closed) Tinzaparin

(Arm Closed) Anticoagulation - intermediate dose thromboprophylaxis

EXPERIMENTAL

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.

Drug: (Arm Closed) Enoxaparin; Drug: (Arm Closed) Dalteparin; Drug: (Arm Closed) Tinzaparin

(Arm Closed) Anticoagulation - therapeutic anticoagulation

EXPERIMENTAL

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

Drug: (Arm Closed) Enoxaparin; Drug: (Arm Closed) Dalteparin; Drug: (Arm Closed) Tinzaparin

(Arm Never Opened) Antibody - Standard of Care

NO INTERVENTION

No hyperimmune globulin

(Arm Never Opened) Antibody - hyperimmune globulin

EXPERIMENTAL

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

Biological: (Arm Never Opened) Hyperimmune globulin

Antiviral II - No antiviral agent

NO INTERVENTION

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

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.

Drug: Nirmatrelvir-Ritonavir

Antiviral II - Remdisivir

EXPERIMENTAL

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.

Drug: Remdesivir

Antiviral II - Nirmatrelvir-ritonavir + remdesivir

EXPERIMENTAL

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

Drug: Nirmatrelvir-Ritonavir; Drug: Remdesivir

Interventions

(Arm Closed) Nafamostat Mesilate DRUG

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.

Also known as: Nafabelltan

(Arm Closed) Antiviral - nafamostat mesilate

(Arm Closed) Enoxaparin DRUG

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) Anticoagulation - intermediate dose thromboprophylaxis; (Arm Closed) Anticoagulation - standard dose thromboprophylaxis; (Arm Closed) Anticoagulation - therapeutic anticoagulation

(Arm Closed) Dalteparin DRUG

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) Anticoagulation - intermediate dose thromboprophylaxis; (Arm Closed) Anticoagulation - standard dose thromboprophylaxis; (Arm Closed) Anticoagulation - therapeutic anticoagulation

(Arm Closed) Tinzaparin DRUG

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; (Arm Closed) Anticoagulation - standard dose thromboprophylaxis; (Arm Closed) Anticoagulation - therapeutic anticoagulation

(Arm Never Opened) Hyperimmune globulin BIOLOGICAL

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

(Arm Never Opened) Antibody - hyperimmune globulin

Nirmatrelvir-Ritonavir DRUG

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.

Also known as: Paxlovid

Antiviral II - Nirmatrelvir-ritonavir; Antiviral II - Nirmatrelvir-ritonavir + remdesivir

Remdesivir DRUG

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.

Also known as: Veklury

Antiviral II - Nirmatrelvir-ritonavir + remdesivir; Antiviral II - Remdisivir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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
• \. Onset of COVID-related symptoms was more than 7 days (i.e., 168 hours) ago
• 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

Sponsors & Collaborators

• University of Melbourne: lead
• The Peter Doherty Institute for Infection and Immunity: collaborator
• Australasian Society for Infectious Diseases: collaborator
• Hunter Medical Research Institute: collaborator
• Aotearoa Clinical Trials: collaborator
• Australian and New Zealand Intensive Care Research Centre: collaborator

Study Sites (25)

Blacktown Hospital

Blacktown, New South Wales, 2148, Australia

Location

Campbelltown Hospital

Campbelltown, New South Wales, 2560, Australia

Location

St Vincent's Hospital Sydney

Darlinghurst, New South Wales, 2010, Australia

Location

Nepean Hospital

Kingswood, New South Wales, 2747, Australia

Location

St George Hospital

Kogarah, New South Wales, 2217, Australia

Location

Liverpool Hospital

Liverpool, New South Wales, 2170, Australia

Location

John Hunter Hospital

New Lambton Heights, New South Wales, 2305, Australia

Location

Prince of Wales Hospital

Randwick, New South Wales, 2031, Australia

Location

Royal North Shore Hospital

St Leonards, New South Wales, 2065, Australia

Location

Wagga Wagga Base Hospital

Wagga Wagga, New South Wales, 2650, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Wollongong Hospital

Wollongong, New South Wales, 2500, Australia

Location

Royal Darwin Hospital

Tiwi, Northern Territory, 0810, Australia

Location

The Prince Charles Hospital

Chermside, Queensland, 4032, Australia

Location

Royal Brisbane and Women's Hospital

Herston, Queensland, 4120, Australia

Location

Lyell McEwin Hospital

Elizabeth Vale, South Australia, 5112, Australia

Location

Ballarat Health Services

Ballarat Central, Victoria, 3350, Australia

Location

Eastern Health (Box Hill Hospital)

Box Hill, Victoria, 3128, Australia

Location

Monash Health

Clayton, Victoria, 3168, Australia

Location

Northern Health

Epping, Victoria, 3076, Australia

Location

Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

Western Health

St Albans, Victoria, 3021, Australia

Location

West Gippsland Hospital

Warragul, Victoria, 3820, Australia

Location

Royal Perth Hospital

Perth, Western Australia, 6000, Australia

Location

Related Publications (4)

• 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.

  PMID: 38320527 DERIVED

• 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.

  PMID: 38320033 DERIVED

• 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.

  PMID: 36514143 DERIVED

• 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.

  PMID: 34953516 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

nafamostat; Enoxaparin; Dalteparin; Tinzaparin; nirmatrelvir and ritonavir drug combination; remdesivir

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-Weight; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Steven Tong, Prof

  Melbourne Health

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This is an open-label study.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Participants enrolled into the study have the option of deciding whether to be randomised in one or more (if available) treatment domains concurrently, if they meet the eligibility criteria.

Study Record Dates

• First Submitted: July 22, 2020
• First Posted: July 23, 2020
• Study Start: July 28, 2020
• Primary Completion: July 25, 2025
• Study Completion: December 31, 2025
• Last Updated: May 16, 2024

Record last verified: 2024-05

Locations

AU (25)