A Phase 2 Safety, Dose-finding and Efficacy Study Evaluating Viscoelastic Testing (VET) Guided Tissue Plasminogen Activator (tPA) Treatment in Critically-ill Pro-thrombotic Acute Respiratory Failure
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Change in clot lysis time on viscoelastic testing from baseline and up to 72 hours
研究概览
简要总结
Patients with coronavirus disease (COVID) and non-COVID acute respiratory failure (ARF) may be at an increased risk of thrombosis due to increased clot formation and decreased clot lysis. This two stage study aims to utilise bedside coagulation technology to detect patients at increased risk and guide tPA treatment to maximise efficacy and safety through a personalised approach.
详细描述
Acute respiratory failure (ARF) due to COVID is associated with an increased risk of thrombosis causing death. Therapeutic heparin administration was not beneficial in the critically ill.
In non-COVID ARF patients, the presence of multiple pulmonary vessel filling defects associated with the severity of disease and patient outcome, and resolved following the administration of the fibrinolytics, streptokinase and urokinase. An early phase I study reported improved oxygenation in patients with severe ARF following administration of plasminogen activators. The rationale for fibrinolytics in ARF has been published previously and is supported by meta-analysis of preclinical studies.
In both non-COVID and COVID associated ARF, defective fibrinolysis has been demonstrated. Standard coagulation tests cannot identify a hypercoagulable state nor assess fibrinolysis whereas viscoelastic testing (VET), a rapid, point-of-care device commonly used in Intensive Care, is able to detect these disorders. Numerous studies have demonstrated that VET is sufficiently sensitive to detect the coagulopathies associated with ARF, with several parameters associating with disease severity.
The VETtiPAT ARF trial uses VET to identify ARF patients with a procoagulant and hypofibrinolytic phenotype, then to guide tPA (Alteplase) administration thus maximising efficacy and safety through a personalised precision medicine approach.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Acute respiratory failure of primary pulmonary infectious or extrapulmonary infectious aetiology with severity graded by the arterial oxygen partial pressure to inspired fraction of oxygen ratio (P/F) as per the Berlin definition: acute onset of hypoxemia with an arterial partial pressure of oxygen (PaO2) to inspired fraction of oxygen (FiO2) ratio of less than or equal to 300 mmHg with positive end expiratory pressure (PEEP) of 5 cm of water (H2O) or greater
- •Requiring admission to Intensive Care
- •Aged 18 - 75 years of age
- •Procoagulant profile on ClotPro (TradeMark) fibrinogen (FIB)-test +/- extrinsic coagulation pathway (EX)-test - above normal range for amplitude at 10 minutes (A10) and/or maximal clot firmness (MCF) at 30 minutes run time
- •Lysis Time on ClotPro tissue plasminogen activator (TPA)-test ClotPro equal to or greater than 365 seconds
排除标准
- •Platelet count <150 x 109/L or a reduction in platelet count of 50% or more in the last 24 hours
- •Body weight < 60 kg
- •Structural intracranial disease e.g. arterio-venous malformation or aneurysm
- •Previous intracranial haemorrhage
- •Ischaemic stroke within 3 months
- •Traumatic cardiopulmonary resuscitation
- •Hypoxaemia from traumatic lung injury
- •Active or recent bleeding
- •Recent surgery, trauma or invasive procedure
- •Systolic blood pressure (BP) > 180 mm Hg
- •Diastolic BP > 100 mm Hg
- •Pericarditis or pericardial fluid
- •Diabetic retinopathy
- •Currently menstruating
- •Pregnancy - (beta-human chorionic gonadotropin (HCG) to be performed if of child-bearing age)
- •Liver failure (known severe liver disease or an alanine aminotransferase or an aspartate aminotransferase level that is 5 times the upper limit of normal)
- •Kidney failure (estimated Glomerular Filtration Rate (eGFR =<30 mL/hr or receiving renal replacement therapy)
- •Use of therapeutic anticoagulation or platelet antagonists
- •Not for active treatment
- •Unlikely to survive until the day after tomorrow
研究组 & 干预措施
VET guided tPA administration + standard care
Actilyse (tPA) will be administered as a 2-hour bolus then low dose infusion over 24 hours (safety and dose-finding stage) and 72 hours (randomised stage). Regular monitoring of the coagulation status and lysis time using VET will enable increases or decreases/cessation of the dose. Prophylactic low molecular weight heparin will continue throughout.
干预措施: Alteplase (Drug)
结局指标
主要结局
Change in clot lysis time on viscoelastic testing from baseline and up to 72 hours
时间窗: From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls
The impact of alteplase administration on the clot lysis time (in seconds) measured by the TPA-test using the ClotPro at the bedside
次要结局
- Change in VET coagulation parameters from baseline and up to 72 hours(From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls)
- Rate of thromboembolic events(From study entry to Day 30 or hospital discharge, whichever occurs first)
- Changes in oxygenation(From start to end of alteplase infusion/ equivalent timeframe in controls)
- Rate of participants with bleeding events(From study entry to Day 5)
- Changes in organ function(From start to end of alteplase infusion/ equivalent timeframe in controls)
研究者
Anders Aneman
Professor
South West Sydney Local Health District