A Multi-centre Randomised Adaptive Platform Clinical Trial to Assess Clinical, Virological and Immunological Outcomes in Patients With SARS-CoV-2 Infection (COVID-19)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 2,200
- 试验地点
- 25
- 主要终点
- 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.
研究概览
简要总结
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).
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This is an open-label study.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A.Core Platform (all participants must meet the following):
- •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):
- •SARS-CoV-2 infection has been confirmed by positive rapid antigen test OR polymerase chain reaction test within the last 7 days
排除标准
- •A. Core platform exclusions (all participants must not meet the following):
- •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
- •Patient is expected to be discharged from hospital today or tomorrow
- •More than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to proven SARS-CoV-2 infection
- •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):
- •Severe renal impairment, defined as eGFR<30ml/min or receipt of renal replacement therapy
- •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.
- •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
- •The patient is known to be pregnant or breastfeeding
- •The treating clinician believes that participation in the domain would not be in the best interests of the patient
- •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):
- •Onset of COVID-related symptoms was more than 7 days (i.e., 168 hours) ago
- •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:
- •No venous access is available and none can be created
- •Known hypersensitivity to remdesivir or its excipients
- •Will be excluded from receiving Nirmatrelvir/ritonavir if:
- •The patient is unable to take, tolerate or absorb oral or enteral medications
- •Known hypersensitivity to any of nirmatrelvir, ritonavir or its excipients
- •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:
- •The patient is in the Immune Suppressed Stratum
- •The patient is receiving or has received supplemental oxygen on the calendar day of eligibility assessment.
- •The patient is considered by the treating clinician to be at very high risk for progression to severe COVID-19
研究组 & 干预措施
(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.
干预措施: (Arm Closed) Nafamostat Mesilate (Drug)
(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.
干预措施: (Arm Closed) Enoxaparin (Drug)
(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.
干预措施: (Arm Closed) Dalteparin (Drug)
(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.
干预措施: (Arm Closed) Tinzaparin (Drug)
(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.
干预措施: (Arm Closed) Enoxaparin (Drug)
(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.
干预措施: (Arm Closed) Dalteparin (Drug)
(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.
干预措施: (Arm Closed) Tinzaparin (Drug)
(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
干预措施: (Arm Closed) Enoxaparin (Drug)
(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
干预措施: (Arm Closed) Dalteparin (Drug)
(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
干预措施: (Arm Closed) Tinzaparin (Drug)
(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
干预措施: (Arm Never Opened) Hyperimmune globulin (Biological)
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.
干预措施: Nirmatrelvir-Ritonavir (Drug)
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.
干预措施: Remdesivir (Drug)
Antiviral II - Nirmatrelvir-ritonavir + remdesivir
Participants will receive both nirmatrelvir-ritonavir and remdesivir using the dose and administration methods described above.
干预措施: Nirmatrelvir-Ritonavir (Drug)
Antiviral II - Nirmatrelvir-ritonavir + remdesivir
Participants will receive both nirmatrelvir-ritonavir and remdesivir using the dose and administration methods described above.
干预措施: Remdesivir (Drug)
结局指标
主要结局
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.
时间窗: 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.
次要结局
- Core Secondary Outcome: WHO 8-point ordinal outcome scale(Day 14)
- Core secondary outcome measures for participants admitted to ICU: ICU length of stay(Up to day 90)
- Antiviral II Domain Secondary Outcome: Proportion of participants with baseline respiratory symptoms in whom all acute respiratory symptoms have resolved at study day 7(Day 7)
- Core Secondary Outcome: Destination at time of hospital discharge(Up to day 90)
- Core secondary outcome measures for participants admitted to ICU: ICU mortality(Up to day 90)
- Core Secondary Outcome: Days alive and free of hospital(Day 28)
- Core Secondary Outcome: Quality of life(Day 180)
- Core Secondary Outcome: Admission (or re-admission) to ICU(During the participant's index hospitalisation. Up to day 90.)
- Core Secondary Outcome: All-cause mortality(Day 28, 90 and 180)
- Core Secondary Outcome: Days alive and free of supplemental oxygen, invasive or non-invasive ventilation(Day 28)
- Core Secondary Outcome: Days alive and free of invasive or non-invasive ventilation or high flow oxygen(Day 28)
- Core secondary outcome measures for participants admitted to ICU: Organ failure free days(Up to day 28)
- Core Secondary Outcome: Days alive and free of invasive mechanical ventilation(Day 28)
- Core Secondary Outcome: Shortness of breath(Day 180)
- Core secondary outcome measures for participants admitted to ICU: Ventilator-free days(Up to day 28)
- Antiviral II Domain Secondary Outcome: Length of hospital stay (in days)(During the participant's index hospitalisation. Censored 90 days after enrolment.)
研究者
Associate Professor Steven Tong
Associate Professor
University of Melbourne