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Viscoelastic Testing Guided Tissue Plasminogen Activator Treatment in Acute Respiratory Failure

PHASE2RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2022-05-18

Primary completion: 2026-05-01

Study completion finish: 2026-12-01

Study type

TREATMENT

Phase

PHASE2

Trial ID

NCT05540834

Intervention or treatment

DRUG: Alteplase

Conditions

• Acute Respiratory Failure
• Hypercoagulability
• Fibrinolysis Shutdown

Image related to Acute Respiratory Failure

Condition: Acute Respiratory Failure, Hypercoagulability and more
DRUG: Alteplase
Liverpool, New South Wales, Australia
Sponsor: South West Sydney Local Health District

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Find a site

Closest Location:

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

Research sites nearby

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/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.
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.	Not specified

Participant Group/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.

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.

Not specified

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Change in clot lysis time on viscoelastic testing from baseline and up to 72 hours	The impact of alteplase administration on the clot lysis time (in seconds) measured by the TPA-test using the ClotPro at the bedside	From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Change in VET coagulation parameters from baseline and up to 72 hours	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	From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls
Changes in oxygenation	Arterial partial pressure of oxygen to inspired fraction of oxygen (P/F) ratio	From start to end of alteplase infusion/ equivalent timeframe in controls
Rate of participants with bleeding events	Any bleeding events Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater	From study entry to Day 5
Rate of thromboembolic events	Any thromboembolic event	From study entry to Day 30 or hospital discharge, whichever occurs first
Changes in organ function	Sequential Organ Failure Assessment (SOFA) score from 0 (normal) to a range of 1-4 with higher scores indicating more severe organ dysfunction	From start to end of alteplase infusion/ equivalent timeframe in controls

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References

Clinical Trials Gov: Viscoelastic Testing Guided Tissue Plasminogen Activator Treatment in Acute Respiratory Failure