Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC), in Collaboration With Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 1,200
- 试验地点
- 60
- 主要终点
- Mortality and days free of organ support
研究概览
简要总结
Endothelial injury as a consequence of SARS-CoV-2 infection leads to a dysregulated host inflammatory response and activation of coagulation pathways. Macro- and micro-vascular thrombosis may contribute to morbidity, organ failure, and death. Therapeutic anticoagulation with heparin may improve clinical outcomes in patients with COVID-19 through anti-thrombotic, anti-inflammatory, and anti-viral activities of heparins. This pragmatic, Bayesian adaptive randomized controlled trial will determine whether therapeutic anticoagulation with heparin (subcutaneous low molecular weight heparin or intravenous unfractionated heparin) versus usual care reduces the need for intubation or death in hospitalized patients with COVID-19. The trial uses an adaptive design which was chosen to overcome limitations in available data to inform a priori estimation of event rates and possible effect sizes. The adaptive design also includes response-adaptive randomization based on baseline D-dimer level, probing for differential efficacy across subgroups defined based on initial D-dimer level. This Bayesian adaptive randomized trial will stop at a conclusion 1) when the posterior probability that the proportional odds ratio is greater than 1.0 reaches 99% (definition of benefit); 2) when the posterior probability that the proportional odds ratio is greater than 1.2 is less than 10% (definition of futility) or; 3) when the posterior probability that the proportional odds ratio is less than 1.0 is greater than 90% (definition of harm). The trial will enroll a maximum of 3,000 patients, although in many simulations the trial may require fewer patients. The trial is strategically aligned with the international REMAP-CAP/COVID platform trial to accelerate evidence generation.
详细描述
This is a prospective, open-label, multicentre, Bayesian adaptive randomized clinical trial to establish whether therapeutic-dose parenteral anticoagulation improves outcomes for patients hospitalized with COVID-19 (e.g., reduces intubation or mortality). Participants will be randomized either to the investigational arm (therapeutic anticoagulation with heparin for 14 days or until "recovery" [defined as hospital discharge or liberation from supplemental oxygen if initially required], whichever comes first), or to the control arm (usual care, including thromboprophylactic dose anticoagulation according to local practice).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
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
- •Patients ≥18 years of age providing (possibly through a substitute decision maker) informed consent who require hospitalization anticipated to last ≥72 hours, for microbiologically-confirmed COVID-19, enrolled < 72 hours of hospital admission or of COVID-19 confirmation
- •If the patient is already hospitalized and the COVID-19 diagnosis is due to an outbreak or an incidental finding, then enrollment can occur within 72 hours of a clinical syndrome attributable to COVID-19 that requires continued hospitalization (e.g. new or worsening oxygen requirements or acute kidney injury) which is further anticipated to extend the hospital admission by an additional 72 hours from randomization.
排除标准
- •Patients admitted to an ICU AND receiving organ support (i.e. high flow nasal oxygen, receiving non-invasive or invasive mechanical ventilation, or are requiring vasopressor/inotrope)
- •Patients for whom the intent is to not use pharmacologic thromboprophylaxis
- •Active bleeding
- •Risk factors for bleeding, including:
- •intracranial surgery or stroke within 3 months;
- •history of intracerebral arteriovenous malformation;
- •cerebral aneurysm or mass lesions of the central nervous system;
- •intracranial malignancy
- •history of intracranial bleeding
- •history of bleeding diatheses (e.g., hemophilia)
- •history of gastrointestinal bleeding within previous 3 months
- •thrombolysis within the previous 7 days
- •presence of an epidural or spinal catheter
- •recent major surgery <14 days
- •uncontrolled hypertension (sBP >200 mmHg, dBP >120 mmHg)
- •other physician-perceived contraindications to anticoagulation
- •Platelet count <50 x10^9/L, INR >2.0, or baseline aPTT >50 (if available per SOC testing)
- •Hemoglobin <80 g/L (to minimize the likelihood of requiring red blood cell transfusion if potential bleeding were to occur)
- •Acute or subacute bacterial endocarditis
- •History of heparin induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity
- •Current use of dual antiplatelet therapy
- •Patients with an independent indication for therapeutic anticoagulation
- •Patients in whom imminent demise is anticipated and there is no commitment to active ongoing intervention
- •Anticipated transfer to another hospital that is not a study site within 72 hours
- •Enrollment in other trials related to anticoagulation or antiplatelet therapy
研究组 & 干预措施
Investigational arm
Participants randomized to the investigational arm will receive therapeutic anticoagulation for 14 days (or until hospital discharge or liberation from supplemental oxygen >24 hours if previously required, whichever comes first) with heparin, with preference for subcutaneous low molecular weight heparin (enoxaparin preferred, although dalteparin or tinzaparin are also acceptable, as available) if no contraindication is present; alternatively, intravenous unfractionated heparin infusion may be used.
干预措施: Heparin (Drug)
结局指标
主要结局
Mortality and days free of organ support
时间窗: 21 days
The primary endpoint in the trial is days alive and free of organ support at day 21. This endpoint is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ support is defined as receipt of invasive or non-invasive mechanical ventilation, high flow nasal oxygen (\>30 L/min), vasopressor therapy, or ECMO support. Death at any time (including beyond 21 days) during the index hospital stay is assigned the worst possible score of -1.
次要结局
- Ischaemic stroke(28 days and 90 days)
- Myocardial infarction(28 days and 90 days)
- Ventilator-free days(28 days)
- Venous thromboembolism(28 days and 90 days)
- Arterial and venous thrombotic conditions(28 days and 90 days)
- Intubation and mortality(30 days)
- All-cause mortality(28 days and 90 days)
- Intubation(30 days)
- Hospital-free days(28 days)
- Vasopressor-free days(28 days)
- Heparin-induced thrombocytopenia (HIT)(Intervention period (maximum 14 days))
- Major bleeding(Intervention period (maximum 14 days))
- Hospital re-admission(28 days)
- Systemic arterial thrombosis or embolism(28 days and 90 days)
- ECMO support(Duration of study)
- Mechanical circuit thrombosis(Duration of study)
- WHO ordinal scale(28 days)
- Renal replacement free days(28 days)
- Acute kidney injury(Duration of study)