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

Sponsor

South West Sydney Local Health District (Other)

Overall Status

Recruiting

CT.gov ID

NCT05540834

Collaborator

(none)

Enrollment

Location

Arms

25.5

Anticipated Duration (Months)

2.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Failure Hypercoagulability Fibrinolysis Shutdown	Drug: Alteplase	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

70 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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.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.

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 18, 2022

Anticipated Primary Completion Date :

May 1, 2024

Anticipated Study Completion Date :

Jul 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Alteplase The enzyme tissue plasminogen activator that cleaves plasminogen to form plasmin. Other Names: Tissue plasminogen activator tPA Actilyse Activase
No Intervention: Standard care 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.

Arm

Intervention/Treatment

Experimental: 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.

Drug: Alteplase

The enzyme tissue plasminogen activator that cleaves plasminogen to form plasmin.

Other Names:

Tissue plasminogen activator

tPA

Actilyse

Activase

No Intervention: Standard care

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.

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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