SARS-CoV-2 Infection (COVID-19)
Conditions
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).
Detailed description
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
Interventions
DRUG(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.
DRUG(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.
DRUG(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.
DRUG(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).
BIOLOGICAL(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
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.
DRUGRemdesivir
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.
Sponsors
The Peter Doherty Institute for Infection and Immunity
Australasian Society for Infectious Diseases
Hunter Medical Research Institute
Aotearoa Clinical Trials
Australian and New Zealand Intensive Care Research Centre
University of Melbourne
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label study.
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
A.Core Platform (all participants must meet the following): 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
A. Core platform exclusions (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 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 B.1. Antiviral II Domain Non-Immune Suppressed Stratum-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Core Secondary Outcome: All-cause mortality | Day 28, 90 and 180 | All participants in the platform will be assessed for this outcome. All-cause mortality |
| Core Secondary Outcome: Days alive and free of hospital | Day 28 | 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. |
| Core Secondary Outcome: Days alive and free of supplemental oxygen, invasive or non-invasive ventilation | Day 28 | 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. |
| Core Secondary Outcome: Days alive and free of invasive or non-invasive ventilation or high flow oxygen | Day 28 | 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 |
| Core Secondary Outcome: Days alive and free of invasive mechanical ventilation | Day 28 | 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. |
| Core Secondary Outcome: Shortness of breath | Day 180 | 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 |
| Core Secondary Outcome: Quality of life | Day 180 | All participants in the platform will be assessed for this outcome. Measured by the EQ-5D-5L questionnaire |
| Core Secondary Outcome: WHO 8-point ordinal outcome scale | Day 14 | 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. |
| Core Secondary Outcome: Admission (or re-admission) to ICU | During the participant's index hospitalisation. Up to day 90. | 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 |
| Core secondary outcome measures for participants admitted to ICU: ICU mortality | Up to day 90 | All participants in the platform who are admitted to ICU will be assessed for this outcome. ICU mortality, censored at 90 days post-randomisation |
| Core secondary outcome measures for participants admitted to ICU: ICU length of stay | Up to day 90 | 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 |
| Core secondary outcome measures for participants admitted to ICU: Ventilator-free days | Up to day 28 | 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 |
| Core secondary outcome measures for participants admitted to ICU: Organ failure free days | Up to day 28 | All participants in the platform who are admitted to ICU will be assessed for this outcome. Number of organ failure free days |
| Antiviral II Domain Secondary Outcome: Length of hospital stay (in days) | During the participant's index hospitalisation. Censored 90 days after enrolment. | All participants randomised to the Antiviral II domain will be assessed for this outcome Number of days in hospital |
| Antiviral II Domain Secondary Outcome: Proportion of participants with baseline respiratory symptoms in whom all acute respiratory symptoms have resolved at study day 7 | 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. |
| Core Secondary Outcome: Destination at time of hospital discharge | Up to day 90 | 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. |
Countries
Australia
Outcome results
None listed