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, 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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
2,200
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.
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.
Blacktown Hospital
Blacktown, New South Wales, Australia
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.
Time frame: Day 21
Core Secondary Outcome: WHO 8-point ordinal outcome scale
All participants in the platform will be assessed for this outcome. The modified ordinal score is: 1. Not hospitalised 2. Hospitalised 3. Hospitalised, requiring supplemental oxygen 4. Hospitalised, on non-invasive ventilation or high flow oxygen devices 5. Hospitalised, on invasive mechanical ventilation or ECMO 6. Death Note. Admission to a Hospital in the Home unit is not counted as hospitalisation for the purposes of this ordinal scale. Patients who have been admitted to hospital and transferred to a Hospital in the Home unit will be assessed as either ordinal score 1 or 2.
Time frame: Day 14
Core Secondary Outcome: All-cause mortality
All participants in the platform will be assessed for this outcome. All-cause mortality
Time frame: Day 28, 90 and 180
Core Secondary Outcome: Days alive and free of hospital
All participants in the platform will be assessed for this outcome. Days alive and free of hospital, as it applies to the index hospital admission, by 28 days after randomisation Note 1. Days spent in a Hospital in the Home unit will not be counted as days in hospital as hospital means 'acute-care hospital' for the purposes of this endpoint. Note 2. If patient is discharged prior to day 28, it will be assumed the patient has not been readmitted to hospital.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
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.
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).
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
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.
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.
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
...and 15 more locations
Time frame: Day 28
Core Secondary Outcome: Days alive and free of supplemental oxygen, invasive or non-invasive ventilation
All participants in the platform will be assessed for this outcome. Number of days alive and free of supplemental oxygen, invasive or non-invasive ventilation by 28 days after randomisation Note. If patient is discharged prior to day 28, it will be assumed that they have not received any supplemental oxygen, invasive or non-invasive ventilation since discharge.
Time frame: Day 28
Core Secondary Outcome: Days alive and free of invasive or non-invasive ventilation or high flow oxygen
All participants in the platform will be assessed for this outcome. Days alive and free of invasive or non-invasive ventilation or high flow oxygen by 28 days after randomisation. Note. If patient is discharged prior to day 28, it will be assumed that they have not received any invasive or non-invasive ventilation since discharge
Time frame: Day 28
Core Secondary Outcome: Days alive and free of invasive mechanical ventilation
All participants in the platform will be assessed for this outcome. Days alive and free of invasive mechanical ventilation by 28 days after randomisation Note. If patient is discharged prior to day 28, it will be assumed that they have not received any invasive ventilation since discharge.
Time frame: Day 28
Core Secondary Outcome: Shortness of breath
All participants in the platform will be assessed for this outcome. A) Dichotomous comparison of a subjective measure of shortness of breath such as: "Are you currently experiencing shortness of breath that you didn't have before you got COVID, or which is worse now than before you got COVID?" B) Ordinal comparison of the modified Medical Research Council (mMRC) breathlessness scale: 0 - I only get breathless with strenuous exercise 1. \- I get short of breath when hurrying on level ground or walking up a slight hill 2. \- On level ground, I walk slower than people of the same age because of breathlessness, or I have to stop for breath when walking at my own pace on the level 3. \- I stop for breath after walking about 100 metres or after a few minutes on level ground 4. \- I am too breathless to leave the house or I am breathless when
Time frame: Day 180
Core Secondary Outcome: Quality of life
All participants in the platform will be assessed for this outcome. Measured by the EQ-5D-5L questionnaire
Time frame: Day 180
Core Secondary Outcome: Destination at time of hospital discharge
All participants in the platform will be assessed for this outcome. Destination characterised as home, rehabilitation hospital, nursing home, or long-term care facility, or another acute hospital.
Time frame: Up to day 90
Core Secondary Outcome: Admission (or re-admission) to ICU
All participants in the platform will be assessed for this outcome. Admission (or re-admission) to ICU during the index hospitalisation, censored at 90 days post-randomisation
Time frame: During the participant's index hospitalisation. Up to day 90.
Core secondary outcome measures for participants admitted to ICU: ICU mortality
All participants in the platform who are admitted to ICU will be assessed for this outcome. ICU mortality, censored at 90 days post-randomisation
Time frame: Up to day 90
Core secondary outcome measures for participants admitted to ICU: ICU length of stay
All participants in the platform who are admitted to ICU will be assessed for this outcome. ICU length of stay, censored at 90 days post-randomisation
Time frame: Up to day 90
Core secondary outcome measures for participants admitted to ICU: Ventilator-free days
All participants in the platform who are admitted to ICU will be assessed for this outcome. Number of ventilator-free days, censored at 28 days post-randomisation
Time frame: Up to day 28
Core secondary outcome measures for participants admitted to ICU: Organ failure free days
All participants in the platform who are admitted to ICU will be assessed for this outcome. Number of organ failure free days
Time frame: Up to day 28
Antiviral II Domain Secondary Outcome: Length of hospital stay (in days)
All participants randomised to the Antiviral II domain will be assessed for this outcome Number of days in hospital
Time frame: During the participant's index hospitalisation. Censored 90 days after enrolment.
Antiviral II Domain Secondary Outcome: Proportion of participants with baseline respiratory symptoms in whom all acute respiratory symptoms have resolved at study day 7
All participants randomised to the Antiviral II domain will be assessed for this outcome Proportion of participants with baseline respiratory symptoms in whom all acute respiratory symptoms have resolved at study day 7 after randomisation. Note 1. Respiratory symptoms are defined as one or more of: cough, sore throat, runny nose sneezing, shortness of breath or chest pain. "Acute" means the symptom in question is not usually present in that individual, or during the current COVID episode was substantially worse or more frequent than usual. Note 2. Resolution of all acute respiratory symptoms means return to baseline state - not necessarily the absence of all respiratory symptoms. Note 3. Ongoing non-respiratory symptoms (such as fatigue, anorexia, delirium, diarrhea) are not counted as part of this endpoint.
Time frame: Day 7