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Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial (ASCOT ADAPT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04483960
Recruitment Status : Recruiting
First Posted : July 23, 2020
Last Update Posted : July 28, 2022
Sponsor:
Collaborators:
The Peter Doherty Institute for Infection and Immunity
Australasian Society for Infectious Diseases
Middlemore Clinical Trials
The George Institute
Hunter Medical Research Institute
The University of Queensland
Information provided by (Responsible Party):
Associate Professor Steven Tong, University of Melbourne

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).

Condition or disease Intervention/treatment Phase
SARS-CoV-2 Infection (COVID-19) Drug: Nafamostat Mesilate Drug: Enoxaparin Drug: Dalteparin Drug: Tinzaparin Biological: Hyperimmune globulin Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2400 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
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.
Masking: None (Open Label)
Masking Description: This is an open-label study.
Primary Purpose: Treatment
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)
Actual Study Start Date : July 28, 2020
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: Antiviral - Standard of care
Standard of care without nafamostat mesilate
Experimental: 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.
Drug: 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.
Other Name: Nafabelltan

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.
Drug: 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: 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: 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).


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.
Drug: 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: 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: 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).


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
Drug: 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: 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: 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).


No Intervention: (Arm Closed) Antibody - Standard of Care
No hyperimmune globulin
Experimental: (Arm Closed) Antibody - hyperimmune globulin
2 doses of 30mL (3x10mL vials) of COVID-19 Hyper-Immunoglobulin (Human) given over 2 days within 48 hours of randomisation
Biological: 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




Primary Outcome Measures :
  1. Death from any cause or requirement of new intensive respiratory support (invasive or non-invasive ventilation) or vasopressor/inotropic support. [ Time Frame: 28 days ]

    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



Secondary Outcome Measures :
  1. Time to clinical recovery [ Time Frame: 28 days ]
    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.

  2. WHO 8-point ordinal outcome scale [ Time Frame: 28 days ]

    The ordinal score is:

    1. Not hospitalised, no limitations on activities
    2. Not hospitalised, limitation on activities
    3. Hospitalised, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection control purposes)
    4. Hospitalised, not requiring supplemental oxygen but requiring ongoing medical care (COVID-19 related or other medical conditions)
    5. Hospitalised, requiring supplemental oxygen
    6. Hospitalised, on non-invasive ventilation or high flow oxygen devices
    7. Hospitalised, on invasive mechanical ventilation or ECMO
    8. 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.


  3. All-cause mortality [ Time Frame: 28 days and 90 days ]
    All-cause mortality

  4. Days alive and free of hospital [ Time Frame: 28 days ]

    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.


  5. Days alive and free of invasive or non-invasive ventilation [ Time Frame: 28 days ]
    Number of days

  6. Shortness of breath [ Time Frame: 28 days and 90 days ]

    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

    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 dressing or undressing

  7. Quality of life [ Time Frame: 28 days and 90 days ]
    Measured by the EQ-5D-5L questionnaire

  8. Antiviral domain-specific outcome: Viral clearance [ Time Frame: 3 and 7 days ]
    Proportion of patients with negative SARS-CoV-2 RT-PCR from upper or lower respiratory tract samples, for those with results available.

  9. Antiviral domain-specific outcome: Viral load [ Time Frame: 3 and 7 days ]
    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.

  10. Antiviral domain-specific outcome: Safety (Liver enzymes) [ Time Frame: Up to day 28 or day of discharge from hospital, whichever is earlier ]
    o Elevation of Alanine Transaminase (ALT) or Aspartate Transaminase (AST) to >5x upper limit of normal

  11. Antiviral domain-specific outcome: Safety (potassium) [ Time Frame: Up to day 28 or day of discharge from hospital, whichever is earlier ]
    o Elevation of serum potassium to >5.5 mmol/L

  12. Antiviral domain-specific outcome: Safety (sodium) [ Time Frame: Up to day 28 or day of discharge from hospital, whichever is earlier ]
    o Decrease of serum sodium to <125 mmol/L

  13. Antiviral domain-specific outcome: Safety (bleeding) [ Time Frame: Up to day 28 or day of discharge from hospital, whichever is earlier ]
    o Major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH).

  14. Antiviral domain-specific outcome: Safety (thrombophlebitis) [ Time Frame: Up to day 28 or day of discharge from hospital, whichever is earlier ]
    o Thrombophlebitis/vasculitis at IV line site

  15. Antiviral domain-specific outcome: serious adverse reactions [ Time Frame: 28 days ]
    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).

  16. Anticoagulation domain-specific outcome: Confirmed deep venous thrombosis [ Time Frame: 28 days ]
    Yes/No

  17. Anticoagulation domain-specific outcome: Confirmed pulmonary embolus [ Time Frame: 28 days ]
    Yes/No

  18. Anticoagulation domain-specific outcome: Confirmed acute myocardial infarction [ Time Frame: 28 days ]
    Yes/No

  19. Anticoagulation domain-specific outcome: Confirmed ischemic cerebrovascular event [ Time Frame: 28 days ]
    Yes/No

  20. Anticoagulation domain-specific outcome: Major bleeding [ Time Frame: 28 days ]
    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.

  21. Anticoagulation domain-specific outcome: Clinically relevant non-major bleeding [ Time Frame: 28 days ]
    Yes/No - As defined by International Society on Thrombosis and Haemostasis (ISTH).

  22. Anticoagulation domain-specific outcome: Heparin-induced thrombocytopenia (HIT) [ Time Frame: 28 days ]
    Yes/No - During index hospitalisation

  23. Anticoagulation domain-specific outcome: Other confirmed thrombotic event [ Time Frame: 28 days ]
    Yes/No - During index hospitalisation

  24. Antibody domain-specific outcome: Serious treatment-related adverse events [ Time Frame: Within 24 hours of treatment ]

    Including:

    1. Serious allergic reaction or anaphylaxis
    2. Transfusion-related acute lung injury (TRALI)

  25. Antibody domain-specific outcome: Haemolysis [ Time Frame: Within 72 hours of last transfusion ]
    Yes/No

  26. Antibody domain-specific outcome: Confirmed arterial thrombosis [ Time Frame: 28 days ]
    Yes/No - acute myocardial infarction, ischaemic cerebrovascular event, other

  27. Antibody domain-specific outcome: Confirmed venous thrombosis [ Time Frame: 28 days ]
    Yes/No - deep vein thrombosis, pulmonary embolus, other



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Platform Inclusion Criteria:

  1. Age ≥ 18 years
  2. Admitted to an acute-care hospital
  3. Confirmed SARS-CoV-2 by nucleic acid testing or rapid antigen testing in the 14 days prior to randomisation
  4. Able to be randomised within 14 days of symptom onset
  5. At least one symptom or sign attributable to SARS-CoV-2 infection

Exclusion Criteria:

A. Overall platform exclusions:

  1. 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.
  2. Previous participation in the trial
  3. Treating team deems enrolment in the study is not in the best interests of the patient
  4. Death is deemed to be imminent and inevitable within the next 24 hours
  5. 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:

  1. 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
  2. Treating team deems enrolment in antibody intervention is not in the best interests of the patient.
  3. Participant has received a SARS-COV-2 vaccine within the prior 30 days
  4. 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
  5. Known personal or religious objections to receiving blood products will exclude a patient from hyperimmune globulin
  6. Pregnant or breastfeeding female participants will be excluded from hyperimmune globulin
  7. 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
  8. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04483960


Contacts
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Contact: Grace McPhee +61 3 8344 3276 grace.mcphee@unimelb.edu.au
Contact: Jocelyn Mora +61 3 8344 0770 jocelyn.mora@unimelb.edu.au

Locations
Show Show 61 study locations
Sponsors and Collaborators
University of Melbourne
The Peter Doherty Institute for Infection and Immunity
Australasian Society for Infectious Diseases
Middlemore Clinical Trials
The George Institute
Hunter Medical Research Institute
The University of Queensland
Investigators
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Study Chair: Steven Tong, A/Prof Melbourne Health
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Associate Professor Steven Tong, Associate Professor, University of Melbourne
ClinicalTrials.gov Identifier: NCT04483960    
Other Study ID Numbers: ERM 62646-A
First Posted: July 23, 2020    Key Record Dates
Last Update Posted: July 28, 2022
Last Verified: July 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Infections
COVID-19
Respiratory Tract Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Nafamostat
Enoxaparin
Dalteparin
Tinzaparin
Heparin, Low-Molecular-Weight
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Protease Inhibitors