Viscoelastic Testing Guided Tissue Plasminogen Activator Treatment in Acute Respiratory Failure

Phase 2

Recruiting

• Conditions: Hypercoagulability; Fibrinolysis Shutdown; Acute Respiratory Failure
• Interventions: Drug: Alteplase

• Registration Number: NCT05540834
• Lead Sponsor: South West Sydney Local Health District

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.

Study Timeline

• Study Start: 2022-05-18
• Study First Submitted: 2022-08-22
• Study First Submitted QC: 2022-09-12
• Study First Posted: 2022-09-15
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-15
• Last Update Posted: 2024-04-17
• Primary Completion: 2026-05-01
• Study Completion: 2026-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 70

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
VET guided tPA administration + standard care	Alteplase	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
Rate of thromboembolic events	From study entry to Day 30 or hospital discharge, whichever occurs first	Any thromboembolic event
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
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

Trial Locations

Locations (1)

Intensive Care Unit, Liverpool Hospital, South Western Sydney Local Health District; 🇦🇺 Liverpool, New South Wales, Australia