Clinical trial NCT05540834: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Respiratory Failure
Hypercoagulability
Fibrinolysis Shutdown
Lead sponsor: South West Sydney Local Health District
Sponsor class: OTHER
First posted: 2022-09-15
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in clot lysis time on viscoelastic testing from baseline and up to 72 hours
timeFrame: From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls
Secondary outcomes:
measure: Change in VET coagulation parameters from baseline and up to 72 hours
timeFrame: From start to end of alteplase infusion + 1 and up to 72 hours later/ equivalent timeframe in controls
measure: Changes in oxygenation
timeFrame: From start to end of alteplase infusion/ equivalent timeframe in controls
measure: Rate of participants with bleeding events
timeFrame: From study entry to Day 5
measure: Rate of thromboembolic events
timeFrame: From study entry to Day 30 or hospital discharge, whichever occurs first
measure: Changes in organ function
timeFrame: From start to end of alteplase infusion/ equivalent timeframe in controls
Other outcomes:
Locations:
city: Liverpool
country: Australia
facility: Intensive Care Unit, Liverpool Hospital, South Western Sydney Local Health District
state: New South Wales
Study officials:
affiliation: Sydney WAHS
name: Anders Aneman
role: PRINCIPAL_INVESTIGATOR
References: