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| Name | Class |
|---|---|
| The Peter Doherty Institute for Infection and Immunity | OTHER |
| Australasian Society for Infectious Diseases | OTHER |
| Hunter Medical Research Institute | UNKNOWN |
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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).
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| (Arm Closed) Antiviral - Standard of care | No Intervention | Standard of care without nafamostat mesilate | |
| (Arm Closed) Antiviral - nafamostat mesilate | Experimental | 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) Anticoagulation - standard dose thromboprophylaxis | Active Comparator | 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. |
|
| (Arm Closed) Anticoagulation - intermediate dose thromboprophylaxis | Experimental | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| (Arm Closed) Nafamostat Mesilate | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
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. |
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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):
B. Antiviral II Domain exclusions (patients at sites participating in the Antiviral II Domain must not meet the following):
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:
Will be excluded from receiving Nirmatrelvir/ritonavir if:
Will be excluded from receiving no antiviral agent if:
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| Name | Affiliation | Role |
|---|---|---|
| Steven Tong, Prof | Melbourne Health | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Blacktown Hospital | Blacktown | New South Wales | 2148 | Australia | ||
| Campbelltown Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38320527 | Derived | Morpeth SC, Venkatesh B, Totterdell JA, McPhee GM, Mahar RK, Jones M, Bandara M, Barina LA, Basnet BK, Bowen AC, Burke AJ, Cochrane B, Denholm JT, Dhungana A, Dore GJ, Dotel R, Duffy E, Dummer J, Foo H, Gilbey TL, Hammond NE, Hudson BJ, Jha V, Jevaji PR, John O, Joshi R, Kang G, Kaur B, Kim S, Das SK, Lau JSY, Littleford R, Marsh JA, Marschner IC, Matthews G, Maze MJ, McArthur CJ, McFadyen JD, McMahon JH, McQuilten ZK, Molton J, Mora JM, Mudaliar V, Nguyen V, O'Sullivan MVN, Pant S, Park JE, Paterson DL, Price DJ, Raymond N, Rees MA, Robinson JO, Rogers BA, Ryu WS, Sasadeusz J, Shum O, Snelling TL, Sommerville C, Trask N, Lewin SR, Hills TE, Davis JS, Roberts JA, Tong SYC. A Randomized Trial of Nafamostat for Covid-19. NEJM Evid. 2023 Nov;2(11):EVIDoa2300132. doi: 10.1056/EVIDoa2300132. Epub 2023 Oct 18. | |
| 38320033 |
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| Aotearoa Clinical Trials |
| OTHER |
| Australian and New Zealand Intensive Care Research Centre | OTHER |
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.
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This is an open-label study.
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| (Arm Closed) Anticoagulation - therapeutic anticoagulation | Experimental | 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 |
|
| (Arm Never Opened) Antibody - Standard of Care | No Intervention | No hyperimmune globulin |
| (Arm Never Opened) Antibody - hyperimmune globulin | Experimental | 2 doses of 30mL (3x10mL vials) of COVID-19 Hyper-Immunoglobulin (Human) given over 2 days within 48 hours of randomisation |
|
| Antiviral II - No antiviral agent | No Intervention | Participants will receive no antiviral agents intended to be active against SARS-CoV-2 for 28 days or until hospital discharge, whichever occurs first. |
| Antiviral II - Nirmatrelvir-ritonavir | Experimental | 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. |
|
| Antiviral II - Remdisivir | Experimental | 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. |
|
| Antiviral II - Nirmatrelvir-ritonavir + remdesivir | Experimental | Participants will receive both nirmatrelvir-ritonavir and remdesivir using the dose and administration methods described above. |
|
|
|
| (Arm Closed) Enoxaparin | Drug | 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 | Drug | 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 | Drug | 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). |
|
| (Arm Never Opened) Hyperimmune globulin | Biological | 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 |
|
| Nirmatrelvir-Ritonavir | Drug | 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 | Drug | 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. |
|
|
| Day 14 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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
| Day 180 |
| 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 |
| 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 |
| 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. |
| 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 |
| 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 |
| 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 |
| 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 |
| 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. |
| 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 |
| Campbelltown |
| New South Wales |
| 2560 |
| Australia |
| St Vincent's Hospital Sydney | Darlinghurst | New South Wales | 2010 | Australia |
| Nepean Hospital | Kingswood | New South Wales | 2747 | Australia |
| St George Hospital | Kogarah | New South Wales | 2217 | Australia |
| Liverpool Hospital | Liverpool | New South Wales | 2170 | Australia |
| John Hunter Hospital | New Lambton Heights | New South Wales | 2305 | Australia |
| Prince of Wales Hospital | Randwick | New South Wales | 2031 | Australia |
| Royal North Shore Hospital | St Leonards | New South Wales | 2065 | Australia |
| Wagga Wagga Base Hospital | Wagga Wagga | New South Wales | 2650 | Australia |
| Westmead Hospital | Westmead | New South Wales | 2145 | Australia |
| Wollongong Hospital | Wollongong | New South Wales | 2500 | Australia |
| Royal Darwin Hospital | Tiwi | Northern Territory | 0810 | Australia |
| The Prince Charles Hospital | Chermside | Queensland | 4032 | Australia |
| Royal Brisbane and Women's Hospital | Herston | Queensland | 4120 | Australia |
| Lyell McEwin Hospital | Elizabeth Vale | South Australia | 5112 | Australia |
| Ballarat Health Services | Ballarat Central | Victoria | 3350 | Australia |
| Eastern Health (Box Hill Hospital) | Box Hill | Victoria | 3128 | Australia |
| Monash Health | Clayton | Victoria | 3168 | Australia |
| Northern Health | Epping | Victoria | 3076 | Australia |
| Alfred Hospital | Melbourne | Victoria | 3004 | Australia |
| Royal Melbourne Hospital | Parkville | Victoria | 3050 | Australia |
| Western Health | St Albans | Victoria | 3021 | Australia |
| West Gippsland Hospital | Warragul | Victoria | 3820 | Australia |
| Royal Perth Hospital | Perth | Western Australia | 6000 | Australia |
| Derived |
| McQuilten ZK, Venkatesh B, Jha V, Roberts J, Morpeth SC, Totterdell JA, McPhee GM, Abraham J, Bam N, Bandara M, Bangi AK, Barina LA, Basnet BK, Bhally H, Bhusal KR, Bogati U, Bowen AC, Burke AJ, Christopher DJ, Chunilal SD, Cochrane B, Curnow JL, Das SK, Dhungana A, Di Tanna GL, Dotel R, DSouza H, Dummer J, Dutta S, Foo H, Gilbey TL, Giles ML, Goli K, Gordon A, Gyanwali P, Haksar D, Hudson BJ, Jani MK, Jevaji PR, Jhawar S, Jindal A, John MJ, John M, John FB, John O, Jones M, Joshi RD, Kamath P, Kang G, Karki AR, Karmalkar AM, Kaur B, Koganti KC, Koshy JM, Krishnamurthy MS, Lau JS, Lewin SR, Lim LL, Marschner IC, Marsh JA, Maze MJ, McGree JM, McMahon JH, Medcalf RL, Merriman EG, Misal AP, Mora JM, Mudaliar VK, Nguyen V, O'Sullivan MV, Pant S, Pant P, Paterson DL, Price DJ, Rees MA, Robinson JO, Rogers BA, Samuel S, Sasadeusz J, Sharma D, Sharma PK, Shrestha R, Shrestha SK, Shrestha P, Shukla U, Shum O, Sommerville C, Spelman T, Sullivan RP, Thatavarthi U, Tran HA, Trask N, Whitehead CL, Mahar RK, Hammond NE, McFadyen JD, Snelling TL, Davis JS, Denholm JT, Tong SYC. Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19. NEJM Evid. 2023 Feb;2(2):EVIDoa2200293. doi: 10.1056/EVIDoa2200293. Epub 2022 Dec 10. |
| 36514143 | Derived | Denholm JT, Venkatesh B, Davis J, Bowen AC, Hammond NE, Jha V, McPhee G, McQuilten Z, O'Sullivan MVN, Paterson D, Price D, Rees M, Roberts J, Jones M, Totterdell J, Snelling T, Trask N, Morpeth S, Tong SY; ASCOT ADAPT investigators. ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial. Trials. 2022 Dec 14;23(1):1014. doi: 10.1186/s13063-022-06929-y. |
| 34953516 | Derived | Bassi A, Arfin S, Joshi R, Bathla N, Hammond NE, Rajbhandari D, Tirupakuzhi Vijayaraghavan BK, Venkatesh B, Jha V. Challenges in operationalising clinical trials in India during the COVID-19 pandemic. Lancet Glob Health. 2022 Mar;10(3):e317-e319. doi: 10.1016/S2214-109X(21)00546-5. Epub 2021 Dec 22. No abstract available. |
| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D014777 | Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| C032855 | nafamostat |
| D017984 | Enoxaparin |
| D017985 | Dalteparin |
| D000078222 | Tinzaparin |
| C000719967 | nirmatrelvir and ritonavir drug combination |
| C000606551 | remdesivir |
| ID | Term |
|---|---|
| D006495 | Heparin, Low-Molecular-Weight |
| D006493 | Heparin |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |
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