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

Primary Purpose

Acute Respiratory Failure, Hypercoagulability, Fibrinolysis Shutdown

Status
Recruiting
Phase
Phase 2
Locations
Australia
Study Type
Interventional
Intervention
Alteplase
Sponsored by
South West Sydney Local Health District
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Respiratory Failure

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

VET guided tPA administration + standard care

Standard care

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
Changes in oxygenation
Arterial partial pressure of oxygen to inspired fraction of oxygen (P/F) ratio
Rate of participants with bleeding events
Any bleeding events Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater
Rate of thromboembolic events
Any thromboembolic event
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

Full Information

First Posted
August 22, 2022
Last Updated
September 15, 2022
Sponsor
South West Sydney Local Health District
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1. Study Identification

Unique Protocol Identification Number
NCT05540834
Brief Title
Viscoelastic Testing Guided Tissue Plasminogen Activator Treatment in Acute Respiratory Failure
Acronym
VETtiPAT-ARF
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 18, 2022 (Actual)
Primary Completion Date
May 2024 (Anticipated)
Study Completion Date
July 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
South West Sydney Local Health District

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Respiratory Failure, Hypercoagulability, Fibrinolysis Shutdown

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
VET guided tPA administration + standard care
Arm Type
Experimental
Arm Description
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.
Arm Title
Standard care
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Alteplase
Other Intervention Name(s)
Tissue plasminogen activator, tPA, Actilyse, Activase
Intervention Description
The enzyme tissue plasminogen activator that cleaves plasminogen to form plasmin.
Primary Outcome Measure Information:
Title
Change in clot lysis time on viscoelastic testing from baseline and up to 72 hours
Description
The impact of alteplase administration on the clot lysis time (in seconds) measured by the TPA-test using the ClotPro at the bedside
Time Frame
From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls
Secondary Outcome Measure Information:
Title
Change in VET coagulation parameters from baseline and up to 72 hours
Description
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
Time Frame
From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls
Title
Changes in oxygenation
Description
Arterial partial pressure of oxygen to inspired fraction of oxygen (P/F) ratio
Time Frame
From start to end of alteplase infusion/ equivalent timeframe in controls
Title
Rate of participants with bleeding events
Description
Any bleeding events Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater
Time Frame
From study entry to Day 5
Title
Rate of thromboembolic events
Description
Any thromboembolic event
Time Frame
From study entry to Day 30 or hospital discharge, whichever occurs first
Title
Changes in organ function
Description
Sequential Organ Failure Assessment (SOFA) score from 0 (normal) to a range of 1-4 with higher scores indicating more severe organ dysfunction
Time Frame
From start to end of alteplase infusion/ equivalent timeframe in controls

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Anders Aneman
Phone
+61 427915693
Email
Anders.Aneman@health.nsw.gov.au
First Name & Middle Initial & Last Name or Official Title & Degree
Lucy Coupland
Phone
+61 419723330
Email
l.coupland@unsw.edu.au
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anders Aneman
Organizational Affiliation
Sydney WAHS
Official's Role
Principal Investigator
Facility Information:
Facility Name
Intensive Care Unit, Liverpool Hospital, South Western Sydney Local Health District
City
Liverpool
State/Province
New South Wales
ZIP/Postal Code
1871
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anders Aneman, MD, PhD
Phone
+61 2 8738 3400
Email
anders.aneman@swsahs.nsw.gov.au

12. IPD Sharing Statement

Plan to Share IPD
No

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Viscoelastic Testing Guided Tissue Plasminogen Activator Treatment in Acute Respiratory Failure

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