Viscoelastic Testing Guided Tissue Plasminogen Activator Treatment in Acute Respiratory Failure (VETtiPAT-ARF)

South West Sydney Local Health District

Status and phase: Enrolling; Phase 2

Conditions: Hypercoagulability; Fibrinolysis Shutdown; Acute Respiratory Failure

Treatments: Drug: Alteplase

Study type: Interventional

Funder types: Other

Identifiers

NCT05540834

ICU001

Details and patient eligibility

About

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.

Full 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.

Enrollment: 70 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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70 participants in 2 patient groups

VET guided tPA administration + standard care

Experimental group

Description:

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.

Treatment:

Drug: Alteplase

Standard care

No Intervention group

Description:

Patients will receive standard care for their condition including prophylactic low molecular weight heparin. Coagulation status and lysis time monitoring with VET will occur at the same times as the experimental arm.