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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04483960




Registration number
NCT04483960
Ethics application status
Date submitted
22/07/2020
Date registered
23/07/2020
Date last updated
16/05/2024

Titles & IDs
Public title
Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial
Scientific 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)
Secondary ID [1] 0 0
X20-0159
Universal Trial Number (UTN)
Trial acronym
ASCOT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
SARS-CoV-2 Infection (COVID-19) 0 0
Condition category
Condition code
Infection 0 0 0 0
Studies of infection and infectious agents
Infection 0 0 0 0
Other infectious diseases
Respiratory 0 0 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - (Arm Closed) Nafamostat Mesilate
Treatment: Drugs - (Arm Closed) Enoxaparin
Treatment: Drugs - (Arm Closed) Dalteparin
Treatment: Drugs - (Arm Closed) Tinzaparin
Treatment: Other - (Arm Never Opened) Hyperimmune globulin
Treatment: Drugs - Nirmatrelvir-Ritonavir
Treatment: Drugs - Remdesivir

No intervention: (Arm Closed) Antiviral - Standard of care - Standard of care without nafamostat mesilate

Experimental: (Arm Closed) Antiviral - 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.

Active comparator: (Arm Closed) Anticoagulation - standard dose thromboprophylaxis - 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.

Experimental: (Arm Closed) Anticoagulation - intermediate dose thromboprophylaxis - 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.

Experimental: (Arm Closed) Anticoagulation - therapeutic anticoagulation - 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

No intervention: (Arm Never Opened) Antibody - Standard of Care - No hyperimmune globulin

Experimental: (Arm Never Opened) Antibody - hyperimmune globulin - 2 doses of 30mL (3x10mL vials) of COVID-19 Hyper-Immunoglobulin (Human) given over 2 days within 48 hours of randomisation

No intervention: Antiviral II - No antiviral agent - Participants will receive no antiviral agents intended to be active against SARS-CoV-2 for 28 days or until hospital discharge, whichever occurs first.

Experimental: Antiviral II - Nirmatrelvir-ritonavir - 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.

Experimental: Antiviral II - Remdisivir - 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.

Experimental: Antiviral II - Nirmatrelvir-ritonavir + remdesivir - Participants will receive both nirmatrelvir-ritonavir and remdesivir using the dose and administration methods described above.


Treatment: Drugs: (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.

Treatment: Drugs: (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.

Treatment: Drugs: (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.

Treatment: Drugs: (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).

Treatment: Other: (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

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
Day 21
Secondary outcome [1] 0 0
Core Secondary Outcome: WHO 8-point ordinal outcome scale
Timepoint [1] 0 0
Day 14
Secondary outcome [2] 0 0
Core Secondary Outcome: All-cause mortality
Timepoint [2] 0 0
Day 28, 90 and 180
Secondary outcome [3] 0 0
Core Secondary Outcome: Days alive and free of hospital
Timepoint [3] 0 0
Day 28
Secondary outcome [4] 0 0
Core Secondary Outcome: Days alive and free of supplemental oxygen, invasive or non-invasive ventilation
Timepoint [4] 0 0
Day 28
Secondary outcome [5] 0 0
Core Secondary Outcome: Days alive and free of invasive or non-invasive ventilation or high flow oxygen
Timepoint [5] 0 0
Day 28
Secondary outcome [6] 0 0
Core Secondary Outcome: Days alive and free of invasive mechanical ventilation
Timepoint [6] 0 0
Day 28
Secondary outcome [7] 0 0
Core Secondary Outcome: Shortness of breath
Timepoint [7] 0 0
Day 180
Secondary outcome [8] 0 0
Core Secondary Outcome: Quality of life
Timepoint [8] 0 0
Day 180
Secondary outcome [9] 0 0
Core Secondary Outcome: Destination at time of hospital discharge
Timepoint [9] 0 0
Up to day 90
Secondary outcome [10] 0 0
Core Secondary Outcome: Admission (or re-admission) to ICU
Timepoint [10] 0 0
During the participant's index hospitalisation. Up to day 90.
Secondary outcome [11] 0 0
Core secondary outcome measures for participants admitted to ICU: ICU mortality
Timepoint [11] 0 0
Up to day 90
Secondary outcome [12] 0 0
Core secondary outcome measures for participants admitted to ICU: ICU length of stay
Timepoint [12] 0 0
Up to day 90
Secondary outcome [13] 0 0
Core secondary outcome measures for participants admitted to ICU: Ventilator-free days
Timepoint [13] 0 0
Up to day 28
Secondary outcome [14] 0 0
Core secondary outcome measures for participants admitted to ICU: Organ failure free days
Timepoint [14] 0 0
Up to day 28
Secondary outcome [15] 0 0
Antiviral II Domain Secondary Outcome: Length of hospital stay (in days)
Timepoint [15] 0 0
During the participant's index hospitalisation. Censored 90 days after enrolment.
Secondary outcome [16] 0 0
Antiviral II Domain Secondary Outcome: Proportion of participants with baseline respiratory symptoms in whom all acute respiratory symptoms have resolved at study day 7
Timepoint [16] 0 0
Day 7

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Blacktown Hospital - Blacktown
Recruitment hospital [2] 0 0
Campbelltown Hospital - Campbelltown
Recruitment hospital [3] 0 0
St Vincent's Hospital Sydney - Darlinghurst
Recruitment hospital [4] 0 0
Nepean Hospital - Kingswood
Recruitment hospital [5] 0 0
St George Hospital - Kogarah
Recruitment hospital [6] 0 0
Liverpool Hospital - Liverpool
Recruitment hospital [7] 0 0
John Hunter Hospital - New Lambton Heights
Recruitment hospital [8] 0 0
Prince of Wales Hospital - Randwick
Recruitment hospital [9] 0 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [10] 0 0
Wagga Wagga Base Hospital - Wagga Wagga
Recruitment hospital [11] 0 0
Westmead Hospital - Westmead
Recruitment hospital [12] 0 0
Wollongong Hospital - Wollongong
Recruitment hospital [13] 0 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [14] 0 0
The Prince Charles Hospital - Chermside
Recruitment hospital [15] 0 0
Royal Brisbane and Women's Hospital - Herston
Recruitment hospital [16] 0 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [17] 0 0
Ballarat Health Services - Ballarat Central
Recruitment hospital [18] 0 0
Eastern Health (Box Hill Hospital) - Box Hill
Recruitment hospital [19] 0 0
Monash Health - Clayton
Recruitment hospital [20] 0 0
Northern Health - Epping
Recruitment hospital [21] 0 0
Alfred Hospital - Melbourne
Recruitment hospital [22] 0 0
Royal Melbourne Hospital - Parkville
Recruitment hospital [23] 0 0
Western Health - St Albans
Recruitment hospital [24] 0 0
West Gippsland Hospital - Warragul
Recruitment hospital [25] 0 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 0 0
2148 - Blacktown
Recruitment postcode(s) [2] 0 0
2560 - Campbelltown
Recruitment postcode(s) [3] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [4] 0 0
2747 - Kingswood
Recruitment postcode(s) [5] 0 0
2217 - Kogarah
Recruitment postcode(s) [6] 0 0
2170 - Liverpool
Recruitment postcode(s) [7] 0 0
2305 - New Lambton Heights
Recruitment postcode(s) [8] 0 0
2031 - Randwick
Recruitment postcode(s) [9] 0 0
2065 - St Leonards
Recruitment postcode(s) [10] 0 0
2650 - Wagga Wagga
Recruitment postcode(s) [11] 0 0
2145 - Westmead
Recruitment postcode(s) [12] 0 0
2500 - Wollongong
Recruitment postcode(s) [13] 0 0
0810 - Tiwi
Recruitment postcode(s) [14] 0 0
4032 - Chermside
Recruitment postcode(s) [15] 0 0
4120 - Herston
Recruitment postcode(s) [16] 0 0
5112 - Elizabeth Vale
Recruitment postcode(s) [17] 0 0
3350 - Ballarat Central
Recruitment postcode(s) [18] 0 0
3128 - Box Hill
Recruitment postcode(s) [19] 0 0
3168 - Clayton
Recruitment postcode(s) [20] 0 0
3076 - Epping
Recruitment postcode(s) [21] 0 0
3004 - Melbourne
Recruitment postcode(s) [22] 0 0
3050 - Parkville
Recruitment postcode(s) [23] 0 0
3021 - St Albans
Recruitment postcode(s) [24] 0 0
3820 - Warragul
Recruitment postcode(s) [25] 0 0
6000 - Perth

Funding & Sponsors
Primary sponsor type
Other
Name
University of Melbourne
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
The Peter Doherty Institute for Infection and Immunity
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Australasian Society for Infectious Diseases
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Hunter Medical Research Institute
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Aotearoa Clinical Trials
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
Australian and New Zealand Intensive Care Research Centre
Address [5] 0 0
Country [5] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Steven Tong, Prof
Address 0 0
Melbourne Health
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.