Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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SARS-CoV-2 Infection (COVID-19)

Intervention / Treatment
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* Drug: Nafamostat Mesilate
* Drug: Enoxaparin
* Drug: Dalteparin
* Drug: Tinzaparin
* Biological: Hyperimmune globulin


Participation Criteria
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Eligibility Criteria
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Platform Inclusion Criteria: Age ≥ 18 years Admitted to an acute-care hospital Confirmed SARS-CoV-2 by nucleic acid testing or rapid antigen testing in the 14 days prior to randomisation Able to be randomised within 14 days of symptom onset At least one symptom or sign attributable to SARS-CoV-2 infection Exclusion Criteria: A. Overall platform exclusions: 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. Previous participation in the trial Treating team deems enrolment in the study is not in the best interests of the patient Death is deemed to be imminent and inevitable within the next 24 hours 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: 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 Treating team deems enrolment in antibody intervention is not in the best interests of the patient. Participant has received a SARS-COV-2 vaccine within the prior 30 days 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 Known personal or religious objections to receiving blood products will exclude a patient from hyperimmune globulin Pregnant or breastfeeding female participants will be excluded from hyperimmune globulin 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Antiviral - Standard of care<br>Standard of care without nafamostat mesilate | |
| Experimental: Antiviral - nafamostat mesilate<br>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: Nafamostat Mesilate<br>* 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.<br>* Other names: Nafabelltan;|
| Active Comparator: (Arm Closed) Anticoagulation - standard dose thromboprophylaxis<br>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. | Drug: Enoxaparin<br>* 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.<br>Drug: Dalteparin<br>* 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.<br>Drug: Tinzaparin<br>* 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).<br>|
| Experimental: (Arm Closed) Anticoagulation - intermediate dose thromboprophylaxis<br>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. | Drug: Enoxaparin<br>* 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.<br>Drug: Dalteparin<br>* 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.<br>Drug: Tinzaparin<br>* 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).<br>|
| Experimental: (Arm Closed) Anticoagulation - therapeutic anticoagulation<br>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 | Drug: Enoxaparin<br>* 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.<br>Drug: Dalteparin<br>* 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.<br>Drug: Tinzaparin<br>* 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).<br>|
| No Intervention: (Arm Closed) Antibody - Standard of Care<br>No hyperimmune globulin | |
| Experimental: (Arm Closed) Antibody - hyperimmune globulin<br>2 doses of 30mL (3x10mL vials) of COVID-19 Hyper-Immunoglobulin (Human) given over 2 days within 48 hours of randomisation | Biological: Hyperimmune globulin<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death from any cause or requirement of new intensive respiratory support (invasive or non-invasive ventilation) or vasopressor/inotropic support. | This includes any participant who receives non-invasive mechanical ventilation (either CPAP or BIPAP, apart from the below considerations) any time after enrolment even if not transferred to ICU. It does NOT include the use of humidified high-flow nasal prong oxygen. Participants on pre-existing home BiPAP or CPAP will not be considered to have met the primary outcome unless they have either i. required invasive mechanical ventilation (i.e. intubation), or ii. graduated from CPAP only whilst asleep to BiPAP at any time, or iii. graduated from BiPAP only whilst asleep to BiPAP for >12 hours/day, or iv. died by day 28 | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to clinical recovery | Defined as the first day, during the 28 days after enrolment, on which a patient satisfies categories 1, 2, or 3 on the WHO eight-point ordinal outcome scale. For the purposes of this outcome measure, it will be assumed that the participant is not hospitalised on the first day following discharge. | 28 days | 
| WHO 8-point ordinal outcome scale | The ordinal score is: Not hospitalised, no limitations on activities Not hospitalised, limitation on activities Hospitalised, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection control purposes) Hospitalised, not requiring supplemental oxygen but requiring ongoing medical care (COVID-19 related or other medical conditions) Hospitalised, requiring supplemental oxygen Hospitalised, on non-invasive ventilation or high flow oxygen devices Hospitalised, on invasive mechanical ventilation or ECMO Death. 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. | 28 days | 
| All-cause mortality | All-cause mortality | 28 days and 90 days | 
| Days alive and free of hospital | Number of days 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. | 28 days | 
| Days alive and free of invasive or non-invasive ventilation | Number of days | 28 days | 
| Shortness of breath | Patient reported outcome. 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? Ordinal comparison of the modified Medical Research Council (mMRC) breathlessness scale: Modified Medical Research Council (mMRC) Dyspnoea Scale for grading the severity of breathlessness during daily activities: 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 dressing or undressing | 28 days and 90 days | 
| Quality of life | Measured by the EQ-5D-5L questionnaire | 28 days and 90 days | 
| Antiviral domain-specific outcome: Viral clearance | Proportion of patients with negative SARS-CoV-2 RT-PCR from upper or lower respiratory tract samples, for those with results available. | 3 and 7 days | 
| Antiviral domain-specific outcome: Viral load | Changes in cycle threshold value in RT-PCR for SARS-CoV-2 from baseline to day 3 and from baseline to day 7, for those with results available from the same respiratory tract sample type. | 3 and 7 days | 
| Antiviral domain-specific outcome: Safety (Liver enzymes) | o Elevation of Alanine Transaminase (ALT) or Aspartate Transaminase (AST) to >5x upper limit of normal | Up to day 28 or day of discharge from hospital, whichever is earlier | 
| Antiviral domain-specific outcome: Safety (potassium) | o Elevation of serum potassium to >5.5 mmol/L | Up to day 28 or day of discharge from hospital, whichever is earlier | 
| Antiviral domain-specific outcome: Safety (sodium) | o Decrease of serum sodium to <125 mmol/L | Up to day 28 or day of discharge from hospital, whichever is earlier | 
| Antiviral domain-specific outcome: Safety (bleeding) | o Major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH). | Up to day 28 or day of discharge from hospital, whichever is earlier | 
| Antiviral domain-specific outcome: Safety (thrombophlebitis) | o Thrombophlebitis/vasculitis at IV line site | Up to day 28 or day of discharge from hospital, whichever is earlier | 
| Antiviral domain-specific outcome: serious adverse reactions | Any safety event that, in the judgment of the investigator, is both serious and either possibly, probably or definitely related to the study intervention(s). | 28 days | 
| Anticoagulation domain-specific outcome: Confirmed deep venous thrombosis | Yes/No | 28 days | 
| Anticoagulation domain-specific outcome: Confirmed pulmonary embolus | Yes/No | 28 days | 
| Anticoagulation domain-specific outcome: Confirmed acute myocardial infarction | Yes/No | 28 days | 
| Anticoagulation domain-specific outcome: Confirmed ischemic cerebrovascular event | Yes/No | 28 days | 
| Anticoagulation domain-specific outcome: Major bleeding | Yes/No - As defined by International Society on Thrombosis and Haemostasis (ISTH). Site of bleeding and which of the ISTH criteria are met will be recorded. | 28 days | 
| Anticoagulation domain-specific outcome: Clinically relevant non-major bleeding | Yes/No - As defined by International Society on Thrombosis and Haemostasis (ISTH). | 28 days | 
| Anticoagulation domain-specific outcome: Heparin-induced thrombocytopenia (HIT) | Yes/No - During index hospitalisation | 28 days | 
| Anticoagulation domain-specific outcome: Other confirmed thrombotic event | Yes/No - During index hospitalisation | 28 days | 
| Antibody domain-specific outcome: Serious treatment-related adverse events | Including: Serious allergic reaction or anaphylaxis Transfusion-related acute lung injury (TRALI) | Within 24 hours of treatment | 
| Antibody domain-specific outcome: Haemolysis | Yes/No | Within 72 hours of last transfusion | 
| Antibody domain-specific outcome: Confirmed arterial thrombosis | Yes/No - acute myocardial infarction, ischaemic cerebrovascular event, other | 28 days | 
| Antibody domain-specific outcome: Confirmed venous thrombosis | Yes/No - deep vein thrombosis, pulmonary embolus, other | 28 days |