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).
ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled adaptive
platform trial. The study design will allow harmonisation with existing frameworks such as
the Sentinel Travellers Research Preparedness Platform for Emerging Infectious Diseases
(SETREP-ID) and the Randomised, embedded, multifactorial adaptive platform trial for
community acquired pneumonia (REMAP-CAP) study.
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. The overarching objective of ASCOT-ADAPT is to identify the regimen (combination of
interventions) associated with the highest chance of survival free of advanced respiratory
support or vasopressor / inotropic support at 28 days after randomisation, in adults
hospitalised with COVID-19 but not requiring ICU-level care at baseline.
In the initial implementation of the adaptive platform, recruiting sites have the option to
participate in one or more of three treatment domains. Consented participants will then be
able to choose whether to be enrolled into one or more available domains concurrently.
Participants will then be randomised to the corresponding interventions:
Intervention domain A (antiviral):
Participants will be randomised using response adaptive randomisation (RAR) on day 1 to
receive either i) standard of care without nafamostat; or ii) standard of care with
nafamostat
(Domain Closed) Intervention domain B (antibody): Participants will be randomised using
response adaptive randomisation (RAR) on day 1 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
using response adaptive randomisation (RAR) on day 1 to receive either i) standard dose
thromboprophylaxis; or ii) intermediate dose thromboprophylaxis; or iii) therapeutic
anticoagulation
Daily data will be collected for the first 28 days or until discharge, whichever is earlier.
There will be a core dataset collected for all patients at all sites and enhanced and
research data and biological samples for sites with capacity. Participants will be followed
up at Day 90.
Drug: 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.
Other Name: Nafabelltan
Drug: 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.
Drug: 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.
Drug: 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).
Biological: 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
Platform Inclusion Criteria:
1. Age ≥ 18 years
2. Admitted to an acute-care hospital
3. Confirmed SARS-CoV-2 by nucleic acid testing or rapid antigen testing in the 14 days
prior to randomisation
4. Able to be randomised within 14 days of symptom onset
5. At least one symptom or sign attributable to SARS-CoV-2 infection
Exclusion Criteria:
A. Overall platform exclusions:
1. Currently receiving acute intensive respiratory support (invasive or non-invasive
mechanical ventilation) or vasopressor/inotropic support. Note, participants already
on community based non-invasive ventilation (either CPAP or BiPAP) can still be
recruited. Humidified high flow nasal oxygen will not be considered an exclusion
criterion.
2. Previous participation in the trial
3. Treating team deems enrolment in the study is not in the best interests of the patient
4. Death is deemed to be imminent and inevitable within the next 24 hours
5. Either the patient or their primary treating clinician are not committed to active
treatment.
This criterion seeks to exclude those patients where supportive comfort measures only are
being provided. Patients who are planned for active ward management with a clear aim to
improve survival, even if intensive care unit level support is not being offered, should
still be included.
B. Domain A (Antiviral) intervention-level exclusions:
Criteria that exclude a patient from one or more interventions are:
Nafamostat:
- Known current decompensated liver disease (Child-Pugh B or C)
- The treating clinician intends to continue or commence therapeutic anticoagulation
- A current or recurrent condition with a high risk of major bleeding (e.g. bleeding
disorder), or a baseline coagulation profile (within the previous 3 days) that
indicates a high risk of bleeding, that would be considered a contraindication to
receive therapeutic anticoagulation
- Serum Potassium >5.5 mmol/L (based on most recent blood test result collected as part
of routine care within the previous 3 days)
- Serum Sodium <120 mmol/L (based on most recent blood test result collected as part of
routine care within the previous 3 days)
- Hypersensitivity to nafamostat
- Pregnancy or breastfeeding
- Currently receiving or have received nafamostat in the past 7 days
- Decompensated heart failure or renal dialysis and clinician believes an extra 500mL
fluid/day would be detrimental There are no domain-level exclusions for the antiviral
domain.
C. Domain B (Antibody - hyperimmunoglobulin or standard care) specific exclusions:
1. Participant has already received treatment with SARS-CoV-2-specific immunoglobulin
therapy (convalescent plasma, hyperimmune globulin or monoclonal antibody) within 3
months prior to enrolment
2. Treating team deems enrolment in antibody intervention is not in the best interests of
the patient.
3. Participant has received a SARS-COV-2 vaccine within the prior 30 days
4. Known previous history of serious allergic reaction to blood product transfusion,
intravenous immunoglobulin or other injectable form of IgG will exclude a patient from
hyperimmune globulin
5. Known personal or religious objections to receiving blood products will exclude a
patient from hyperimmune globulin
6. Pregnant or breastfeeding female participants will be excluded from hyperimmune
globulin
7. Prior history of a thrombotic event (including acute coronary syndromes,
cerebrovascular syndromes, pulmonary or deep vein thrombosis) within the prior 30 days
of randomisation will exclude a patient from receiving hyperimmune globulin
8. Having a creatinine clearance of less than 50mL/min will exclude a patient from
receiving hyperimmune globulin
D. Domain C (Anticoagulation) domain-level exclusions:
Patients will be excluded from this domain if they have any of the following:
- Receiving dual antiplatelet therapy
- The treating clinician intends to continue or commence therapeutic anticoagulation
- Contraindication to receiving low molecular weight heparin or unfractionated heparin,
including the known or suspected history of heparin-induced thrombocytopenia or other
adverse reaction to prior heparin exposure such as hypersensitivity
- Severe thrombocytopenia (platelet count less than 530 x 109/L)
- History of intracranial haemorrhage in the previous 3 months
- Severe renal impairment, defined as estimated glomerular filtration rate less than
15ml/min/1.73m2
- A current or recurrent condition with a high risk of major bleeding (e.g. bleeding
disorder), or a baseline coagulation profile (within the previous 3 days) that
indicates a high risk of bleeding, that would be considered a contraindication to
receive therapeutic anticoagulation
Calvary Public Bruce Hospital
Bruce, Australian Capital Territory, Australia
The Canberra Hospital
Canberra, Australian Capital Territory, Australia
Armidale Hospital
Armidale, New South Wales, Australia
Bankstown-Lidcombe Hospital
Bankstown, New South Wales, Australia
Blacktown Hospital
Blacktown, New South Wales, Australia
Campbelltown Hospital
Campbelltown, New South Wales, Australia
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
The Sutherland Hospital
Caringbah, New South Wales, Australia
Coffs Harbour Health Campus
Coffs Harbour, New South Wales, Australia
St Vincent's Hospital Sydney
Darlinghurst, New South Wales, Australia
Northern Beaches Hospital
Frenchs Forest, New South Wales, Australia
Griffith Base Hospital
Griffith, New South Wales, Australia
Hornsby Ku-Ring Gai Hospital
Hornsby, 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
Orange Health Service
Orange, New South Wales, Australia
Port Macquarie Base Hospital
Port Macquarie, New South Wales, Australia
Prince of Wales Hospital
Randwick, New South Wales, Australia
Royal North Shore Hospital
St Leonards, New South Wales, Australia
The Tweed Hospital
Tweed Heads, New South Wales, Australia
Wagga Wagga Base Hospital
Wagga Wagga, New South Wales, Australia
Calvary Mater Newcastle
Waratah, 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
Sunshine Coast University Hospital
Birtinya, Queensland, Australia
The Prince Charles Hospital
Chermside, Queensland, Australia
Royal Brisbane and Women's Hospital
Herston, Queensland, Australia
Gold Coast University Hospital
Southport, Queensland, Australia
Lyell McEwin Hospital
Elizabeth Vale, South Australia, Australia
Royal Hobart Hospital
Hobart, Tasmania, Australia
Launceston General Hospital
Launceston, Tasmania, Australia
Ballarat Health Services
Ballarat Central, Victoria, Australia
St John of God Ballarat Hospital
Ballarat, Victoria, Australia
Bendigo Health
Bendigo, Victoria, Australia
Eastern Health (Box Hill Hospital)
Box Hill, Victoria, Australia
Monash Health
Clayton, Victoria, Australia
Northern Health
Epping, Victoria, Australia
St. Vincent's Hospital Melbourne
Fitzroy, Victoria, Australia
Frankston Hospital - Penninsula Health
Frankston, Victoria, Australia
Peninsula Private Hospital
Frankston, Victoria, Australia
Barwon Health - University Hospital Geelong
Geelong, Victoria, Australia
Austin Health
Heidelberg, Victoria, Australia
Cabrini Health
Malvern, Victoria, Australia
Alfred Hospital
Melbourne, Victoria, Australia
Royal Melbourne Hospital
Parkville, Victoria, Australia
Epworth Richmond
Richmond, Victoria, Australia
Goulburn Valley Health
Shepparton, Victoria, Australia
Western Health
St Albans, Victoria, Australia
Latrobe Regional Hospital
Traralgon, Victoria, Australia
West Gippsland Hospital
Warragul, Victoria, Australia
Albury Wodonga Health
Wodonga, Victoria, Australia
Rockingham General Hospital
Cooloongup, Western Australia, Australia
Joondalup Health Campus
Joondalup, Western Australia, Australia
Armadale Health Service
Mount Nasura, Western Australia, Australia
Fiona Stanley Hospita
Murdoch, Western Australia, Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia
Royal Perth Hospital
Perth, Western Australia, Australia
St John of God Subiaco Hospital
Subiaco, Western Australia, Australia
Grace McPhee
+61 3 8344 3276
grace.mcphee@unimelb.edu.au
Jocelyn Mora
+61 3 8344 0770
jocelyn.mora@unimelb.edu.au
Steven Tong, A/Prof, Study Chair
Melbourne Health