Viscoelastic Testing Guided Tissue Plasminogen Activator Treatment in Acute Respiratory Failure

Official title

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

Overview

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

• Drug Alteplase
  The enzyme tissue plasminogen activator that cleaves plasminogen to form plasmin.

Primary outcome measures

• Change in clot lysis time on viscoelastic testing from baseline and up to 72 hours [Time frame: From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls]

Secondary outcome measures (5)

• Change in VET coagulation parameters from baseline and up to 72 hours [Time frame: From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls]
• Changes in oxygenation [Time frame: From start to end of alteplase infusion/ equivalent timeframe in controls]
• Rate of participants with bleeding events [Time frame: From study entry to Day 5]
• Rate of thromboembolic events [Time frame: From study entry to Day 30 or hospital discharge, whichever occurs first]
• Changes in organ function [Time frame: From start to end of alteplase infusion/ equivalent timeframe in controls]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 1 center

• Intensive Care Unit, Liverpool Hospital, South Western Sydney Local Health District — Liverpool

Publications

• Coupland LA, Rabbolini DJ, Schoenecker JG, Crispin PJ, Miller JJ, Ghent T, Medcalf RL, Aneman AE. Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study. Crit Care. 2023 Feb 10;27(1):55. doi: 10.1186/s13054-023-04329-5. PMID 36765421

Identifiers

NCT: NCT05540834 · ICU001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗