Viscoelastic Testing Guided Tissue Plasminogen Activator Treatment in Acute Respiratory Failure

NCT ID: NCT05540834

Last Updated: 2024-04-17

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 70 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-18
• Study Completion Date: 2026-12-01

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.

Conditions

Acute Respiratory Failure; Hypercoagulability; Fibrinolysis Shutdown

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Alteplase

Intervention Type: DRUG

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

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Alteplase

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

Intervention Type: DRUG

Other Intervention Names

Tissue plasminogen activator; tPA; Actilyse; Activase

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

South West Sydney Local Health District

OTHER

Sponsor Role: lead

Responsible Party

Anders Aneman

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Anders Aneman

Role: PRINCIPAL_INVESTIGATOR

Sydney WAHS

Locations

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

Liverpool, New South Wales, Australia

Site Status: RECRUITING

Countries

Australia

Central Contacts

Anders Aneman

Role: CONTACT

Anders.Aneman@health.nsw.gov.au

+61 427915693

Lucy Coupland

Role: CONTACT

l.coupland@unsw.edu.au

+61 419723330

Facility Contacts

Anders Aneman, MD, PhD

Role: primary

anders.aneman@swsahs.nsw.gov.au

+61 2 8738 3400

References

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.

Reference Type: DERIVED

PMID: 36765421 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

ICU001

Identifier Type: -

Identifier Source: org_study_id