Acute Respiratory Failure, Fibrinolysis Shutdown, Hypercoagulability
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGAlteplase
The enzyme tissue plasminogen activator that cleaves plasminogen to form plasmin.
Sponsors
South West Sydney Local Health District
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A two stage study evaluating (1) safety and dose-finding of escalating Actilyse (tPA) doses, followed by (2) a randomised, controlled efficacy study of VET-guided Actilyse treatment + standard care VERSUS standard care alone.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. 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 2. Requiring admission to Intensive Care 3. Aged 18 - 75 years of age 4. 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 5. Lysis Time on ClotPro tissue plasminogen activator (TPA)-test ClotPro equal to or greater than 365 seconds
Exclusion criteria
1. Platelet count \<150 x 109/L or a reduction in platelet count of 50% or more in the last 24 hours 2. Body weight \< 60 kg 3. Structural intracranial disease e.g. arterio-venous malformation or aneurysm 4. Previous intracranial haemorrhage 5. Ischaemic stroke within 3 months 6. Traumatic cardiopulmonary resuscitation 7. Hypoxaemia from traumatic lung injury 8. Active or recent bleeding 9. Recent surgery, trauma or invasive procedure 10. Systolic blood pressure (BP) \> 180 mm Hg 11. Diastolic BP \> 100 mm Hg 12. Pericarditis or pericardial fluid 13. Diabetic retinopathy 14. Currently menstruating 15. Pregnancy - (beta-human chorionic gonadotropin (HCG) to be performed if of child-bearing age) 16. Liver failure (known severe liver disease or an alanine aminotransferase or an aspartate aminotransferase level that is 5 times the upper limit of normal) 17. Kidney failure (estimated Glomerular Filtration Rate (eGFR =\<30 mL/hr or receiving renal replacement therapy) 18. Use of therapeutic anticoagulation or platelet antagonists 19. Not for active treatment 20. Unlikely to survive until the day after tomorrow
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in clot lysis time on viscoelastic testing 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 | The impact of alteplase administration on the clot lysis time (in seconds) measured by the TPA-test using the ClotPro at the bedside |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | The impact of alteplase administration on clot formation related to fibrinogen and the extrinsic pathway (maximum clot firmness (MCF) / amplitude at 10 minutes (A10) in millimeters) measured by the FIB-test and EX-test using the ClotPro at the bedside |
| Changes in oxygenation | From start to end of alteplase infusion/ equivalent timeframe in controls | Arterial partial pressure of oxygen to inspired fraction of oxygen (P/F) ratio |
| Rate of participants with bleeding events | From study entry to Day 5 | Any bleeding events Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater |
| Rate of thromboembolic events | From study entry to Day 30 or hospital discharge, whichever occurs first | Any thromboembolic event |
| Changes in organ function | From start to end of alteplase infusion/ equivalent timeframe in controls | Sequential Organ Failure Assessment (SOFA) score from 0 (normal) to a range of 1-4 with higher scores indicating more severe organ dysfunction |
Countries
Australia
Contacts
Primary ContactAnders Aneman
Backup ContactLucy Coupland
Outcome results
None listed