Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial

SARS-CoV-2 Infection (COVID-19) Clinical Trial

— ASCOT  

Official title:

A Multi-centre Randomised Adaptive Platform Clinical Trial to Assess Clinical, Virological and Immunological Outcomes in Patients With SARS-CoV-2 Infection (COVID-19)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04483960
• Other study ID #: X20-0159
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 28, 2020
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: University of Melbourne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 2200
• Est. completion date: December 31, 2025
• Est. primary completion date: July 25, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 Exclusion Criteria (all non-immune suppressed patients at sites participating in the Antiviral II Domain must not

meet the following):

1. Onset of COVID-related symptoms was more than 7 days (i.e., 168 hours) ago B2. Antiviral II domain Intervention-specific Exclusion Criteria (All patients at sites participating in the Antiviral II Domain will be excluded from the below interventions if they meet the following):

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

Related Conditions & MeSH terms

• COVID-19
• Infections
• SARS-CoV-2 Infection (COVID-19)

Intervention

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.
• (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).

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

Drug:
• 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.

Locations

Country	Name	City	State
Australia	Ballarat Health Services	Ballarat Central	Victoria
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Eastern Health (Box Hill Hospital)	Box Hill	Victoria
Australia	Campbelltown Hospital	Campbelltown	New South Wales
Australia	The Prince Charles Hospital	Chermside	Queensland
Australia	Monash Health	Clayton	Victoria
Australia	St Vincent's Hospital Sydney	Darlinghurst	New South Wales
Australia	Lyell McEwin Hospital	Elizabeth Vale	South Australia
Australia	Northern Health	Epping	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	St George Hospital	Kogarah	New South Wales
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Alfred Hospital	Melbourne	Victoria
Australia	John Hunter Hospital	New Lambton Heights	New South Wales
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Western Health	St Albans	Victoria
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	Royal Darwin Hospital	Tiwi	Northern Territory
Australia	Wagga Wagga Base Hospital	Wagga Wagga	New South Wales
Australia	West Gippsland Hospital	Warragul	Victoria
Australia	Westmead Hospital	Westmead	New South Wales
Australia	Wollongong Hospital	Wollongong	New South Wales

Sponsors (6)

Lead Sponsor	Collaborator
University of Melbourne	Aotearoa Clinical Trials, Australasian Society for Infectious Diseases, Australian and New Zealand Intensive Care Research Centre, Hunter Medical Research Institute, The Peter Doherty Institute for Infection and Immunity

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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: Not hospitalised; Hospitalised; Hospitalised, requiring supplemental oxygen; Hospitalised, on non-invasive ventilation or high flow oxygen devices; Hospitalised, on invasive mechanical ventilation or ECMO; 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.	Day 14
Secondary	Core Secondary Outcome: All-cause mortality	All participants in the platform will be assessed for this outcome.; All-cause mortality	Day 28, 90 and 180
Secondary	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.	Day 28
Secondary	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.	Day 28
Secondary	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	Day 28
Secondary	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.	Day 28
Secondary	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; - I get short of breath when hurrying on level ground or walking up a slight hill; - 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; - I stop for breath after walking about 100 metres or after a few minutes on level ground; - I am too breathless to leave the house or I am breathless when	Day 180
Secondary	Core Secondary Outcome: Quality of life	All participants in the platform will be assessed for this outcome.; Measured by the EQ-5D-5L questionnaire	Day 180
Secondary	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.	Up to day 90
Secondary	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	During the participant's index hospitalisation. Up to day 90.
Secondary	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	Up to day 90
Secondary	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	Up to day 90
Secondary	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	Up to day 28
Secondary	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	Up to day 28
Secondary	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	During the participant's index hospitalisation. Censored 90 days after enrolment.
Secondary	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.	Day 7