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
Phase: PHASE2
Conditions: Acute Respiratory Failure, Hypercoagulability, Fibrinolysis Shutdown
Sponsor: South West Sydney Local Health District

 
VETtiPAT ARF 
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A Phase 2 safety, dose-finding and efficacy study evaluating 
viscoelastic testing (VET) guided tissue plasminogen activator (tPA) 
treatment in critically-ill patients with pro-thrombotic acute 
respiratory failure (ARF) . 
 
  
‘VETtiPAT ARF’ 
 
Protocol #: ICU001 
 
NCT: to be assigned, version 4.1, posted on the 7th of September 2022 
 
Sponsor: South Western Sydney Local Health District 
 
Coordinating Principal Investigator: Clinical  
Prof Anders Aneman, Senior Intensive Care Specialist, ICU Research Director, Liverpool Hospital 
Senior Fellow, Simpson Centre for Health Services Research 
Ingham Institute for Applied Medical Research 
Ph: 0427 915 693; Email: Anders.Aneman@health.nsw.gov.au 
 
Coordinating Principal Investigator: Non-Clinical 
Dr Lucy Coupland, Senior Clinical Research Scientist, Liverpool ICU,  
Maridulu Budyari Gumal SPHERE Clinical Trials Methodology Hub Coordinator 
Ingham Insitute for Applied Medical Research, UNSW SWS Medical School 
Ph: 0419 723 330; Email: l.coupland@unsw.edu.au 
 
Principal Investigator (Bankstown Hospital) 
TBC , ICU Bankstown Hospital 
 
 
Co-Investigators: 
Dr Steve Frost, ICU RN, Liverpool Hospital, Epidemiologist WSU  
Dr David Rabbolini, Haematologist and ClotPro expert, Lismore Hospital 
Ms Ainslie Cahill AM, Consumer and Community Representative 
Mr Tony Ghent, Coagulation Laboratory Scientist and independent ClotPro consultant 
Dr Jonathan Williamson, Respiratory Physician, Liverpool Hospital 
Dr Melissa Baraket, Respitatory Physician, Liverpool Hospital 
Dr Danny Hsu, Haematologist, Liverpool Hospital 
 
Locations of Study: 
Liverpool Hospital Intensive Care Unit 
Bankstown Hospital Intensive Care Unit 
 

 
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1.0 
SUMMARY ....................................................................................................................................... 4 
2.0 
BACKGROUND - ARDS ...................................................................................................................... 5 
2.1 
Viscoelastic Testing (VET) ................................................................................................................. 6 
2.2 
VET in ARDS ..................................................................................................................................... 6 
2.3  
Plasma tPA and PAI-1 levels in ARDS ................................................................................................ 8 
2.4 
tPA treatment for myocardial infarction, stroke and pulmonary embolism ...................................... 8 
2.5 
tPA treatment in ARDS ..................................................................................................................... 8 
2.6 
Current Clinical Trials with tPA in COVID-19 patients ........................................................................ 9 
2.7 
How will this study contribute to the field? .................................................................................... 10 
3.0 
STUDY AIMS & HYPOTHESES .......................................................................................................... 10 
4.0 
PARTICIPATING SITES ..................................................................................................................... 10 
5.0 
STUDY DESIGN ............................................................................................................................... 10 
6.0 
EXPECTED DURATION .................................................................................................................... 11 
7.0 
PATIENT POPULATION ................................................................................................................... 11 
8.0 
ELIGIBILITY CRITERIA ...................................................................................................................... 11 
8.1 
Inclusion Criteria ............................................................................................................................ 11 
8.2 
Exclusion Criteria ........................................................................................................................... 11 
9.0 
STUDY OUTLINE & PROCEDURES .................................................................................................... 12 
9.1 
Stage 1: Safety & Alteplase Dose-Finding ....................................................................................... 12 
9.2 
Stage 2: Phase II Randomised, Controlled, Open-Label Trial ........................................................... 14 
10.0 
STUDY OUTCOME MEASURES ........................................................................................................ 15 
10.1 
Primary Outcome Measure ............................................................................................................ 15 
10.2 
Secondary Outcome Measures ....................................................................................................... 15 
11.0 
STATISTICAL CONSIDERATIONS ...................................................................................................... 15 
11.1 
Sample Size and Power .................................................................................................................. 15 
12.0 
CONSENT PROCESS ........................................................................................................................ 16 

 
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13.0 
RANDOMISATION PROCESS ........................................................................................................... 16 
14.0 
ETHICAL CONSIDERATIONS ............................................................................................................ 17 
14.1  
Ethics Review ................................................................................................................................. 17 
15.0 
REPORTING of SERIOUS ADVERSE EVENTS and BLEEDING EVENTS ................................................. 17 
Definition of Serious Adverse Events ........................................................................................................... 17 
15.1 
Reporting of bleeding events ......................................................................................................... 17 
16.0 
STUDY OVERSIGHT and INDEPENDENT MONITORING .................................................................... 18 
17.0 
STUDY PROCEDURE BENEFITS ........................................................................................................ 18 
18.0 
STUDY PROCEDURE RISKS .............................................................................................................. 18 
19.0 
CONFIDENTIALITY & PRIVACY ........................................................................................................ 19 
19.1 
Data Collection and Storage ........................................................................................................... 19 
19.2  
Retention of Records ..................................................................................................................... 19 
19.3  
Disclosure and Confidentiality ....................................................................................................... 19 
20.0 
STUDY TERMINATION .................................................................................................................... 20 
21.0 
FUNDING ....................................................................................................................................... 20 
22.0 
RESEARCH OUTCOMES ................................................................................................................... 20 
23.0  
QUALITY CONTROL AND ASSURANCE ............................................................................................. 20 
23.1  
Compliance with Regulations ......................................................................................................... 20 
24.0  
SPONSOR AND INVESTIGATOR OBLIGATIONS ................................................................................... 21 
24.1  
Protocol Amendments ................................................................................................................... 21 
24.2  
Protocol Deviations ........................................................................................................................ 21 
25.0 
REFERENCES ................................................................................................................................... 21 
26.0  
Appendix 1: Anticoagulant and Platelet-Antagonists ......................................................................... 24 
 
 

 
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1.0 
SUMMARY 
 
Study Title 
A Phase 2 safety, dose-finding and efficacy study evaluating 
viscoelastic testing (VET) guided tissue plasminogen activator (tPA) 
treatment in critically-ill patients with pro-thrombotic acute 
respiratory failure (ARF) . 
 
Aims/Objectives 
To determine whether the administration of alteplase normalises 
fibrinolysis in patients with ARF and a hypercoagulant and 
hypofibrinolytic disease phenotype, thus at high risk of thrombosis. 
 
Stage 1: establish the safety and dose range of VET-guided alteplase 
treatment in ARF patients at high risk of thrombosis. 
 
Stage 2: determine whether the administration of alteplase to ARF 
patients at high risk of thrombosis normalises fibrinolysis and 
improves organ function. 
   
Study design 
This is a phase II clinical trial which will be conducted in 2 stages: 
Stage 1 is a safety and dose-finding stage involving 4 groups of 5 
patients. 
Stage 2 is a randomised, controlled, open-label trial of alteplase. 
 
Planned sample size 
Stage 1: 20 participants 
Stage 2: 50 participants 
 
Eligibility Criteria 
Inclusion criteria 
 
 
1. Diagnosis of acute respiratory failure (ARF) with severity graded 
by the arterial oxygen partial pressure to inspired fraction of 
oxygen ratio (PaO2/FiO2) 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 H2O 
or greater. The ARF may be of primary pulmonary infectious or 
extrapulmonary infectious aetiology. 
 
2. Requiring admission to the Intensive Care Unit (ICU) 
3. Aged 18 – 75 years of age 
4. Procoagulant profile on ClotPro Fib-test +/- EX-test – above 
normal range for A10 and/or MCF at 30 mins 
5. Lysis Time on ClotPro TPA-TEST ClotPro equal to or greater than 
365 seconds  
 
Exclusion criteria 
1. Platelet count < 125 x 109/L or a reduction in platelet count of 50 
x 109/L or more within last 24 hours. 
2. Body weight < 60 kg 
3. Structural intracranial disease e.g. arterio-venous malformation 
or aneurysm 
4. Previous intracranial haemorrhage 

 
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5. Ischaemic stroke within 3 months 
6. Primary and/or metastatic solid tumours 
7. Traumatic cardiopulmonary resuscitation 
8.  Hypoxaemia from traumatic lung injury  
9. Active or recent bleeding 
10. Surgery, trauma or invasive procedure within 4 weeks – if after 
this period, consult surgeon first. 
11. Systolic BP > 180 mm Hg 
12. Diastolic BP > 100 mm Hg 
13. Pericarditis or pericardial fluid 
14. Diabetic retinopathy 
15. Currently menstruating 
16. Pregnancy – (bHCG to be performed if of child-bearing age)  
17. Liver failure (known severe liver disease or an alanine 
aminotransferase or an aspartate aminotransferase level that is 5 
times the upper limit of normal) 
18. Kidney failure (estimated Glomerular Filtration Rate (eGFR £30 
mL/hr or receiving renal replacement therapy) 
19. Use of therapeutic anticoagulation or platelet antagonists (see 
Appendix 1) 
20. Not for active treatment 
21. Unlikely to survive until the day after tomorrow 
 
Study intervention 
The study will be conducted in two stages: the first, a safety and dose-
finding stage of escalating alteplase doses, and the second a 
randomised, controlled, open-label, Phase II clinical trial comparing 
VET-guided alteplase treatment with the dose tailored according to 
the patients lysis time on VET + standard care, with standard care 
alone in the same patient disease group. 
Study duration 
Approximately 24 months 
 
 
2.0 
BACKGROUND - ARF 
Acute respiratory failure (ARF) most commonly develops in response to infection or a systemic 
inflammatory state. A recent and prominent example of infectious ARF is caused by  COVID-19 and is 
characterised by progressive respiratory failure and a distinct coagulopathy. A study of 184 COVID-19 
patients admitted to Intensive Care revealed a thrombotic complication rate of 31% [1]. Autopsies 
conducted on COVID-19 patients have demonstrated widespread thrombosis throughout the lungs [2, 
3], and a deep vein thrombosis rate of 58% with pulmonary embolism the cause of death in 30% [4].  
Elevated D-dimer levels, a byproduct of clot breakdown, is associated with poor patient outcomes in 
COVID-19 patients, with some critically-ill patients have D-dimer levels  well above the detection limits 
of standard laboratory testing [5, 6].  
 
Other non-COVID-19 infectious forms of ARF are also associated with a pro-coagulant phenotype [7, 
8]. In the 1980’s several pulmonary angiography studies were undertaken in ARF patients 
demonstrating the presence of multiple pulmonary vessel filling defects that associated with the 
severity of disease and patient outcome [9-11], and that resolved following the administration of the 
fibrinolytics, streptokinase and urokinase [12]. An early phase I study reported improved oxygenation 
in patients with severe ARF following administration of plasminogen activators [13]. The rationale for 

 
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fibrinolytics in ARF has been published previously [[14, 15] and is supported by a meta-analysis of 
preclinical studies [16]. 
 
In both non-COVID-19 and COVID-19 associated ARF, defective natural fibrinolysis has been 
demonstrated [17-23]. If fibrinolysis (clot breakdown) becomes compromised, as is seen in ARF 
patients, D-Dimer levels may not reflect the full extent of thrombosis present, thus they are not an 
accurate indicator of the severity of disease. Standard coagulation tests are also unhelpful in these 
patients as they cannot identify a hypercoagulable state nor assess fibrinolysis. 
 
 
2.1 
Viscoelastic Testing (VET) 
Viscoelastic testing (VET) is a proven point-of-care technology approved by the TGA for the global 
assessment of whole blood coagulation.  In contrast to standard coagulation testing, VET is able to 
provide insight into procoagulant phenotypes, fibrinolysis, the extrinsic and intrinsic coagulation 
pathways, fibrin clot formation, platelet contribution to clot formation, tissue plasminogen activator 
sensitivity and more. As a point-of-care device it has a rapid turn-around time of 10 minutes for initial 
information on clotting status. 
 
VET has improved internationally the anticoagulation and blood product transfusion practices in 
cardiac bypass surgery, trauma and liver failure [24].  It is already used extensively to guide patient 
care in the above-mentioned indications at the Liverpool Hospital Intensive Care Unit.   
 
2.2 
VET in ARF  
Numerous studies have demonstrated that VET is sufficiently sensitive to detect the coagulopathies 
associated with ARF, with several parameters associating with the severity of disease [23, 25]. Studies 
in COVID-19 patients consistently show increased clot dimensions and strength on Ex-Test, as depicted 
in Figure 1, with reduced clot lysis upon tPA challenge, TPA-Test, as depicted in Figure 2. Table 1 
summarises the results of TPA-tests in COVID-19 patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal control 
COVID-19 Patients 

 
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Figure 1: ClotPro results demonstrating hypercoagulation in COVID-19 patients 
Upon addition of tissue factor to blood (Ex-Test), clot formation occurs and key parameters can be 
measured such as time to onset of clotting (CT), amplitude of the clot at 5 (A5) and 10 (A10) min 
following the onset of clotting, and maximum clot firmness (MCF) [26]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2: ClotPro results demonstrating hypofibrinolysis in COVID-19 patients 
The TPA-Test involves the addition of tPA and tissue factor to the blood sample then measuring the 
clotting response. In healthy subjects (top left panel), the clot is lysed by tPA as it forms, whereas in 
COVID-19 patients, clot lysis occurs slowly (bottom right panel) or not at all (top right panel). Lysis 
Time (LT) is a measure of the time taken for the maximum clot firmness to decrease by 50% [23].  
 
 
 
Table 1: TPA-Test Lysis Time (seconds) in COVID-19 patients and healthy controls 
 
 
COVID-19 patients 
 
Healthy Controls 
 
Difference 
(95% CI), p-value 
 
Reference 
 
530 +/- SD 327, n=27 
Critically ill 
 
211 +/- SD 80, n=12 
 
319 (182,456), p<0.001 
 
[20] 
 
400 +/- SD 93, n=7 
Critically ill 
 
201 +/- SD 63, n=15 
 
199 (111, 287), p<0.001 
 
[21] 
 
368 +/- SD 125, n=7 
Non-critically ill 
 
201 +/- SD 63, n=15 
(same cohort as above) 
 
167 (50, 284), p<0.001 
 
[21] 
 
508 (365 – 827), n=20 
(25th – 75th percentile) 
Critically ill 
 
210 (186-261), n=60 
(25th – 75th percentile) 
 
298 (151, 445), p<0.001 
 
[22] 
 
             TPA Challenge using TPA-Test 
Normal 
COVID-19  
Patients 
COVID-19  
Patients

 
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2.3  
Plasma tPA and PAI-1 levels in ARF  
Plasminogen activator inhibitor-1 (PAI-1) is released from platelets, innate immune cells, endothelium 
and hepatocytes and is elevated in infection [27]. Circulating PAI-1 was found to be elevated in severe 
pneumonia and non-COVID-19 ARF, as a result of release from alveolar macrophages, while 
endothelial cells produced lower levels of tissue plasminogen activator (tPA), thus creating a pro-
thrombotic state [19]. In ARF injury, PAI-1 levels in pulmonary fluid was found to correlate with 
mortality [28].  
 
VET and non-VET studies have demonstrated a resistance of clots from COVID-19 patients to the 
fibrinolytic effects of added tissue plasminogen activator (tPA) reflecting the presence of high levels 
of PAI-1 [23, 26].  A study examining tPA and PAI-1 levels in COVID-19 patients demonstrated that high 
levels of both these factors were associated with severe disease and death. While some patients had 
high tPA levels thus a hyperfibrinolytic bleeding disease phenotype, others had high PAI-1 levels and 
a hypofibrinolytic thrombotic disease phenotype [26].   
 
These data demonstrate that coagulopathy occurs with all forms of ARF.A personalised approach to 
the management of coagulopathic ARF patients is essential and this can only be achieved in a clinically-
relevant timeframe with the use of VET. 
 
2.4 
tPA treatment for myocardial infarction, stroke and pulmonary embolism 
tPA is standard treatment for myocardial infarction and stroke and has demonstrated substantial 
benefit in preserving functional tissue in the heart and brain through the lysis of blood clots blocking 
arteries to these essential organs [29, 30]. The most commonly used protocol in both situations is to 
infuse 0.9 mg/kg (maximum dose 90 mg)  intravenously over 1 hr with 10% of the total dose 
administered as an initial bolus over 1 minute [31]. 
 
Patients with pulmonary embolism also benefit significantly from treatment with thrombolytic 
therapy including tPA [32]. A low-dose (50mg infusion over 2 hr) was found to be equally effective as 
a high-dose (100 mg infusion over 2 hr) with a reduced incidence of bleeding in a meta-analysis of 
trials [33].  
 
 
2.5 
tPA treatment in ARF 
Unlike myocardial infarction, stroke and PE, infectious ARF is associated with a disseminated and 
ongoing coagulopathy due to severe infection and the immune system response. Several animal 
models of ARF [16, 34, 35] and small studies in non-COVID-19 ARF patients using fibrinolytic therapy 
have demonstrated clearance of microthrombii from within the pulmonary vasculature and improved 
lung function [12, 36, 37]. The reason that fibrinolytic therapy has not been adopted as standard 
treatment for ARF is the potential bleeding risk [38], despite no bleeding episodes occurring in a study 
of 18 ARF patients [37]. A keen but cautious interest remains in the use of tPA for non-COVID-19 ARF.  
 
In a small series of COVID-19 patients with ARF, 2 of 3 patients received temporary benefit, in the form 
of improved lung function, from the administration of tPA 25 mg as a i.v. bolus then a further 25 mg 
over 24 hr as an i.v. infusion without any bleeding complications occurring [39]. In the US, tPA was 
considered an option for COVID-19 in desperate times when ICU- and ventilator beds were exhausted 
[40]. Given the pathophysiology of COVID-19 disease, there is significant interest in the use of 
thrombolytics, however, the selection of patients most likely to benefit from this treatment based 
upon standard laboratory testing is considered problematic [40, 41].  

 
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VET, more specifically ClotPro, has been shown capable of distinguishing between the hyper- and 
hypolytic and hyper- and hypocoagulant phenotypes in COVID-19, and therefore identifying patients 
who will most likely benefit from tPA treatment. Of equal importance, VET will also identify patients 
who have a bleeding risk and, hence, who should not receive tPA treatment. In terms of optimising 
the treatment effect and minimising bleeding risk, ClotPro provides the ability to quantify the 
response to tPA therapy thus permitting dose titration. 
 
 
2.6 
Current Clinical Trials with tPA in COVID-19 patients 
 
The following is a summary of clinical trials that are using thrombolytics in COVID-19 patients and that 
are entered into the international ClinicalTrials.gov website. There are currently no studies registered 
using thrombolytics in non-COVID-19 ARF. 
 
In situ thrombolysis with tPA and inflow perfusion analysis in patient with severe COVID-19 
infection. 
This was a compassionate study undertaken in Mexico in 15 patients who had tPA injected directly 
into their pulmonary arteries under fluoroscopic guidance and an assessment of efficacy made on 
the distribution of contrast before and after the procedure. 
 
This trial is complete but no results are provided. 
 
A study to test whether different doses of Alteplase (tPA) help people with severe breathing 
problems because of COVID-19 (TRISTARDS) 
This Boehringer Ingelheim sponsored study being conducted in Europe is recruiting and is 
described as administering a low-dose or high-dose alteplase infusion for 5 days on top of 
standard care. The dose details are not provided. An interim analysis of Phase IIb of this study, 
that included 62 patients randomised to receive 1 of 2 dosing regimes of alteplase for up to 5 days 
in combination with standard of care or standard of care alone, demonstrated favourable safety 
and efficacy data (https://www.boehringer-ingelheim.com/press-release/bi-focuses-covid-19-
clinical-research-alteplase). 
 
Tenecteplase in patients with COVID-19 
This placebo controlled study to be conducted in Israel is determining the efficacy of the longer-
acting thrombolytic agent, Tenecteplase, in COVID-19 patients with respiratory failure. There will 
be 2 active treatment groups who will receive low- (0.25 mg/kg) or high-dose (0.5 mg/kg) 
Tenecteplase as an i.v. bolus in combination with heparin.   
 
Fibrinolytic therapy to treat ARF in the setting of COVID-19 infection 
This randomised controlled study to be conducted in the US will have 2 active treatment groups. 
The first group will receive tPA treatment 50 mg administered as an i.v. bolus (10 mg) followed by 
the remaining 40 mg given as in infusion over 2 hr. Immediately afterwards patients will 
commence on an i.v. heparin infusion. Patients may receive an additional 50 mg between 24 and 
36 hr if an improvement in PaO2/FiO2 is seen.  The second group will receive a tPA infusion of 2 
mg/hr for a 24 hr period after the initial bolus and 2 hr infusion. Following the 24 hr infusion of 
tPA, patients are commenced on an i.v. heparin infusion. This study is active but not recruiting 
[42, 43]. 

 
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2.7 
How will this study contribute to the field? 
The last 3 studies summarised above will be recruiting patients based upon their D-dimer levels +/- 
evidence of PE on CTPA +/- the level of respiratory dysfunction. D-dimers levels reflect clot breakdown, 
or fibrinolysis. When the system is overwhelmed however, as is seen in ARF patients, fibrinolysis is 
compromised thus the level of D-dimers does not necessarily reflect the levels of thrombosis.  
Critically-ill ARF patients are not routinely screened for pulmonary emboli as this would delay the 
commencement of life-saving treatment. The degree of respiratory distress is not an accurate 
measure of the need for tPA administration as it may be due to the bacterial/viral load, immune 
response, and/or pre-existing lung conditions as well as thrombotic processes.  
 
This study will be recruiting patients admitted to the ICU with ARF based upon their VET results, 
specifically, the demonstration of a pro-coagulant profile on the FIB-Test +/- EX-Test, and delayed lysis 
on the TPA-Test. In the TPA-Test, the blood sample is supplemented with tPA. Delayed lysis provides 
further evidence of a pro-coagulant phenotype and the length of time required for lysis to occur 
provides a measure of the severity of fibrinolysis shutdown.  We will, therefore, be selecting patients 
who may benefit from tPA treatment using a direct measure in real-time of coagulation and 
fibrinolysis. In addition to this targeted patient selection process, VET will be employed to closely 
monitor the response of each patient to tPA treatment and the dose tailored according to this 
response.  This personalised approach to tPA therapy is similar to the management of i.v. heparin 
where the dose is dictated by aPTT levels, whereas in this case, Lysis Time will be dictating tPA dosing. 
This will significantly increase the likelihood of a therapeutic dose being delivered and decrease the 
risk of bleeding. Such an approach to tPA treatment has not been previously undertaken, thus this 
study will potentially provide a new protocol for improved tPA administration. It will also add 
significant insight into the kinetics of the reversal of fibrinolysis imbalance in severe infection through 
tPA supplementation. 
 
 
3.0 
STUDY AIMS & HYPOTHESES 
The aims of this study are to: 
  
(i) 
Stage 1: establish the safety and dose range of VET-guided alteplase treatment in ARF patients 
at high risk of thrombosis. 
 
(ii) 
Stage 2: determine whether the administration of alteplase to ARF patients at high risk of 
thrombosis normalises fibrinolysis and improves organ function.  
 
The hypothesis underpinning the study aims is that the administration of alteplase will restore the 
tPA/PAI-1 balance allowing fibrinolytic activity to occur normally, thus preventing thrombosis-induced 
ischaemia of organs and poor patient outcomes. 
 
 
4.0 
PARTICIPATING SITES 
The study will be conducted in the Intensive Care Units of Liverpool and Bankstown Hospitals, NSW. 
 
 
5.0 
STUDY DESIGN 
The study will be conducted in 2 stages: 

 
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Stage 1 is a safety and dose-finding stage involving 4 groups of 5 patients. 
Stage 2 is a Phase II, randomised, controlled, open-label trial. 
 
6.0 
EXPECTED DURATION 
It is anticipated this study will commence in January 2022 and be completed in 2023. 
 
 
7.0 
PATIENT POPULATION 
Patients who are admitted to the Intensive Care Units at Liverpool and Bankstown Hospitals will 
undergo routine viscoelastic testing for a broad assessment of coagulation status.  The ClotPro 
machine will be used for this study as it offers a TPA-Test to assess fibrinolysis along with the EX-Test 
and Fib-Test. Those patients who are identified as being hypercoagulant and hypofibrinolytic on VET 
testing will be considered suitable for further screening.  
 
 
8.0 
ELIGIBILITY CRITERIA 
 
8.1 
Inclusion Criteria 
1. Diagnosis of acute respiratory failure (ARF) with severity graded by the arterial oxygen partial 
pressure to inspired fraction of oxygen ratio (PaO2/FiO2) 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 H2O or greater. The ARF may be of primary pulmonary infectious or 
extrapulmonary infectious aetiology. 
 
2. Requiring admission to Intensive Care 
3. Aged 18 – 75 years of age 
4. Procoagulant profile on ClotPro Fib-test +/- EX-test – above normal range for A10 and/or MCF 
at 30 mins run time 
5. Lysis Time on ClotPro TPA-TEST ClotPro equal to or greater than 365 seconds  
 
 
8.2 
Exclusion Criteria 
1. Platelet count <125 x 109/L or a reduction in platelet count of 50 x 109/L  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. Primary and/or metastatic solid tumours 
7. Traumatic cardiopulmonary resuscitation 
8. Hypoxaemia from traumatic lung injury 
9. Active or recent bleeding 
10. Surgery, trauma or invasive procedure within 4 weeks – if after this period, consult 
surgeon first. 
11. Systolic BP > 180 mm Hg 
12. Diastolic BP > 100 mm Hg 
13. Pericarditis or pericardial fluid 

 
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14. Diabetic retinopathy 
15. Currently menstruating 
16. Pregnancy – (bHCG to be performed if of child-bearing age)  
17. Liver failure (known severe liver disease or an alanine aminotransferase or an aspartate 
aminotransferase level that is 5 times the upper limit of normal) 
18. Kidney failure (estimated Glomerular Filtration Rate (eGFR £30 mL/hr or receiving renal 
replacement therapy) 
19. Use of therapeutic anticoagulation or platelet antagonists (see Appendix 1) 
20. Not for active treatment 
21. Unlikely to survive until the day after tomorrow 
 
9.0 
STUDY OUTLINE & PROCEDURES 
This trial will consist of 2 stages, the first a safety and dose-finding stage, and the second a randomised, 
controlled trial of VET-guided alteplase treatment + standard care versus standard care alone.  
 
9.1 
Stage 1: Safety & Alteplase Dose-Finding 
Upon admission to ICU, all ARF patients will have a 2.7 mL blood sample collected to enable baseline 
VET analysis which would include: EX-Test, plasminogen-test, Fib-Test, TPA-Test run over 30 minutes. 
This aspect of the trial will not require consent as VET is part of routine ICU assessment in patients 
with a potential coagulopathy. Weight will be estimated and a urinalysis via dipstick will be undertaken 
as per standard care to confirm the absence of haematuria.  
 
The VET results will be used to identify patients who are hypercoagulopathic (Ex-Test parameters) and 
hypofibrinolytic (Lysis Time on TPA-Test of equal to or greater than 365 seconds) thus at high risk of 
organ damage due to micro- and macro-thromboembolism. 
 
Group 1 will consist of 5 participants who will receive the following treatment after being screened 
for eligibility and consented to the study: 
  
› alteplase treatment will commence with an i.v. infusion of 25 mg over 2 hr, then an i.v. 
infusion of 1 mg /hr for 22 hr*  
› VET will be repeated at 3, 6, 12, 18 and 24 hr post-infusion commencement, and 1 hr post 
cessation. Alteplase is rapidly cleared by the liver with a half-life of 4-10 minutes thus a 
coagulation profile will be obtained following 24 hr of, and then in the absence of alteplase 
administration. 
 
* Total dose over 24 hr = 47 mg. 
 
Group 2 will consist of 5 participants who will receive the following treatment after being screened 
for eligibility and consented to the study: 
 
› alteplase treatment commenced with an i.v. infusion of 50 mg over 2 hr, then an infusion of 
2 mg/hr over 22 hr*  
› VET will be repeated at 3, 6, 12, 18 and 24 hr post-infusion commencement, and 1 hr post 
cessation. 
 
* Total dose over 24 hr = 94 mg. 
 
Depending upon the results obtained in the first 2 groups of patients:  

 
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Group 3 will consist of 5 participants who will be selected based upon a Lysis Time on the TPA-test of 
426 – 500 seconds. Following screening for eligibility and consent to the study they will receive: 
  
› alteplase treatment commenced with an i.v. infusion of 50 mg over 2 hours, then an infusion 
of 4 mg/hr mg over 22 hr* 
› VET will be repeated at 3, 6, 12, 18 and 24 hr post-infusion commencement, and 1 hr post 
cessation. 
 
*   Total dose over 24 hr = 138 mg 
 
 
Group 4 will consist of 5 participants who will be selected based upon a Lysis Time on the TPA-test of  
>500 seconds. Following screening for eligibility and consent to the study they will receive: 
 
› alteplase treatment commenced with an i.v. infusion of 50 mg over 2 hours, then an infusion 
of 4 mg/hr over 22 hr* 
› VET will be repeated at 3, 6, 12, 18 and 24 hr post-infusion commencement, and 1 hr post 
cessation 
› if VET results at 12 hr have not improved from baseline, a 25 mg alteplase i.v. bolus will be 
administered and the infusion and VET monitoring continued. 
 
* Total dose over 24 hr = 138 +/- 25 mg.  
 
***In all of the above dosing schedules, the maximum alteplase dose administered within the first 2 
hours is less than the dose administered within 1 hr for myocardial infarction or stroke under standard 
tPA treatment protocols (0.9 mg/kg with a maximum of 90 mg).  
 
****The half-life of alteplase is very short being 4-10 minutes. 
 
Treatment Stopping Rules: 
Alteplase treatment will be ceased should any of the following events occur: 
› Lysis Time on repeat TPA-Test is less than 250 seconds 
› Grade 2+ bleeding event (CTCAE grading system, see below: Reporting of Serious Adverse 
Events) 
› Reduction in platelet count to <100 x 109/L. 
› Decision by the attending Intensive Care Specialist 
› All participants should be continued on venous thromboembolism (VTE) prophylaxis as per 
standard care (s.c. low-molecular weight heparin (LMWH) / unfractionated heparin (UF) 
throughout). 
 
 
 
 

 
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9.2 
Stage 2: Phase II Randomised, Controlled, Open-Label Trial 
 
Patients randomised to receive alteplase treatment 
The following protocol, including alteplase doses and timing of repeat VET testing, will be reconsidered 
in the light of results obtained from Stage 1. 
 
Upon admission to ICU, all ARF patients will have a 2.7 mL blood sample collected to enable baseline 
VET analysis which would include: EX-Test, plasminogen-test, Fib-Test, TPA-Test run over 30 minutes. 
This aspect of the trial will not require consent as VET is part of routine ICU assessment in patients 
with a potential coagulopathy. Weight will be estimated and urinalysis via dipstick will also be 
undertaken as per standard care to confirm the absence of haematuria. 
 
The VET results would be used to identify patients who are hypercoagulopathic and hypofibrinolytic 
and thus, at high risk of organ damage due to micro- and macro-thromboembolism. Patients will be 
consented and randomised to receive standard anticoagulation or VET-guided alteplase treatment.  
 
Participants randomised to the alteplase arm will be commenced on alteplase treatment according to 
the lysis time on TPA-Test as per the following treatment chart: 
 
Chart 1: Alteplase Treatment Commencement Guide 
Lysis Time on TPA-Test of 365 – 425 seconds 
50 mg i.v. infusion over 2 hr, then 2 mg/hr i.v. infusion 
Lysis Time on TPA-Test of 426 – 500 seconds 
50 mg i.v. infusion over 2 hr, then 4 mg/hr i.v. infusion 
Lysis Time on TPA-Test of greater than 500 seconds 
50 mg i.v. infusion over 1 hr, then 4 mg/hr i.v. infusion over 24 hr 
 
Every 6 hours post-infusion commencement, VET will be repeated on all patients: 
 
› If the Lysis Time is less than 250 seconds the alteplase infusion will be ceased and 6 hrly VET 
monitoring continued**. 
 
› If the Lysis Time is 250 - 364 seconds the alteplase infusion will be reduced to 1mg/hr.  
 
› If the Lysis Time is between 365 – 425 seconds, the alteplase infusion will remain at, or be 
changed to 2 mg / hr. 
 
› If the Lysis Time is between 426 and 500 seconds, the alteplase infusion will remain at, or be 
changed to 4 mg / hr. 
 
› If the Lysis Time is greater than 500 seconds, an alteplase bolus of 25 mg will be administered 
i.v. over 1 min and the i.v. alteplase  infusion continued at 4 mg / hr. 
 
 
* alteplase treatment will continue for a maximum of 72 hours following the study start time with 
a minimum of 6 hrly VET monitoring throughout this period* 
 
**If within the 72 hr treatment period, the Lysis Time increases above 365 seconds in a patient 
where the alteplase was previously ceased, alteplase should be recommenced at 2 mg/hr. 
 

 
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Treatment Stopping Rules: 
Alteplase treatment will be permanently ceased should any of the following events occur: 
› Reduction in platelet count to <100 x 109/L. 
› Grade 2+ bleeding event (CTCAE grading system, see below: Reporting of Serious Adverse 
Events) 
› 72 hours of alteplase treatment has been administered 
› Decision by the attending Intensive Care Specialist 
 
All participants should continue VTE prophylaxis throughout the alteplase treatment period. 
 
VET will be repeated on all participants 24 hr following cessation of the alteplase treatment period. 
 
 
Participants Randomised to the Standard Control Arm 
VET will be conducted every 6 hours for a 72 hr period then again at 96 hr following consent. 
 
 
10.0 STUDY OUTCOME MEASURES 
 
10.1 
Primary Outcome Measure 
Changes in Lysis Time on TPA-Test from baseline to 72 hours 
 
10.2 
Secondary Outcome Measures 
Changes in all other VET parameters from baseline to 72 hours 
Incidence of thromboembolism to 30 days or hospital discharge, whichever occurs first 
Incidence of bleeding requiring medical intervention to 5 days post alteplase cessation 
Changes in organ function – lung, liver, kidneys, haematology (PaO2/FiO2 ratio and SOFA scores) from 
baseline to 72 hours 
 
 
11.0 STATISTICAL CONSIDERATIONS 
Results will be reported using descriptive statistics for normally and non-normally distributed data. 
Comparison between groups will be performed using non-paired t-testing as appropriate for normally 
(Student t-test) or non-normally (Mann-Whitney U-test) distributed data. Repeated measurements 
will be reported using mixed factor analysis of variance (ANOVA) with time as within-subjects factor 
and group (tPA dose or tPA vs. standard care alone) as between-subjects factor. 
 
In Stage 2 of the study, participants will be randomised on a 1:1 ratio to receive alteplase treatment + 
standard care or standard care alone.  
 
An interim analysis will occur once 50% of patients (12 in each arm) have been recruited to the study 
enabling the reassessment of safety and early detection of detriment, futility or benefit of alteplase 
treatment.   
 
11.1 
Sample Size and Power 
Based on the primary outcome of interest, a sample size of 25 study participants in each arm of the 
study, will have a power of 0.99 and 0.94 to detect a 2-SD and 1-SD (125 seconds, cf. Table 1) 
difference in TPA-test lysis time between the intervention and control participants, respectively. 

 
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12.0 CONSENT PROCESS 
The consent process for this clinical trial will be tailored to the physical status of the patient. 
Additionally, the patients may be in isolation if infected with COVID-19 in which case the ICU specialists 
will consent in one of the manners outlined below:  
1. Patients in ICU not on a ventilator or heavily sedated:  The ICU specialist will provide a copy 
of the Participant Information and Consent Form (PICF) to the patient and discuss the clinical 
trial with them. The patient will be given the opportunity to ask questions and consider 
participating in the study. They will be advised that participation is voluntary and they can 
withdraw at any time. If the patient is willing to participate in the clinical trial the ICU Specialist 
and the patient will sign the consent form. If the patient has COVID-19, a photo of the consent 
form will be taken as the PICF cannot be removed from the isolation room. A copy of this will 
be sent to the patient and filed in their medical records. 
 
2. Patients in ICU ventilated or heavily sedated with a responsible person present in the hospital: 
The ICU specialist will provide a copy of the PICF to the responsible person and discuss the 
clinical trial with them. The responsible person will be given the opportunity to ask questions 
and consider whether the patient should participate. The responsible person will be advised 
that participation is voluntary, the patient can be withdrawn at any time and that if they 
decide not to participate they will receive alternative treatments. If the responsible person is 
willing to consent to the patient being involved in the clinical trial the PICF will be signed. A 
copy will be provided to the responsible person. When the patient has sufficiently recovered 
the PICF will be provided to the patient and if the patient is willing to participate in the clinical 
trial the ICU Specialist and the patient will sign the consent form. In the event the patient is 
not willing to consent, the study staff and Sponsor will be notified that the data cannot be 
used. 
 
3. Patients in ICU ventilated or heavily sedated with a responsible person not available to meet 
with the ICU Specialist face to face: The ICU specialist will contact the responsible person via 
telephone and discuss the clinical trial with them. A copy of the PICF will be emailed to the 
responsible person and s/he will be given the opportunity to ask questions and consider 
whether the patient should participate. The responsible person will be advised that 
participation is voluntary, the patient can be withdrawn at any time and that if they decide 
not to participate they will receive alternative treatments. The ICU Specialist will arrange a 
video conference with the responsible person once they have had time to review the 
information and via video conference the responsible person is willing to consent to the 
patient being involved in the clinical trial. This video conference will be recorded and used as 
oral consent and filed in the patient’s medical records and the Investigator Site File. A copy 
will be provided to the responsible person. When the patient has sufficiently recovered the 
PICF will be provided to the patient and if the patient is willing to participate in the clinical 
trial the ICU Specialist and the patient will sign the consent form. In the event the patient is 
not willing to consent, the study staff and Sponsor will be notified that the data cannot be 
used. 
 
13.0 RANDOMISATION PROCESS 
A computer generated randomisation list will be used to assign patients to standard care or alteplase 
treatment.  
 

 
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14.0 ETHICAL CONSIDERATIONS 
While alteplase administration is an experimental treatment approach in ARF patients, the logic is 
sound given the pathophysiology and the evidence of a significant pro-thrombotic risk associated with 
COVID-19 and other lung infections, and there is evidence of benefit from animal studies and small-
scale clinical trials. 
 
Alteplase is not an experimental medicine having been used for several decades in patients suffering 
myocardial infarction, stroke or pulmonary embolism. For myocardial infarction and stroke, the 
amount of alteplase used is higher and delivered over a shorter time frame than what is proposed in 
this study which has been designed to be more in line with protocols for pulmonary embolism. 
 
This study is taking advantage of VET technology to increase the safety and efficacy of alteplase 
treatment in this population. VET will ensure that patients at greatest risk of thrombosis are selected 
for screening, and will eliminate those patients at risk of bleeding complications.  Additionally, ongoing 
VET testing throughout the alteplase treatment period will ensure an optimal dose is delivered thus 
minimising the risk of over-dosing with potential bleeding complications, but also reducing the 
likelihood of under-dosing and having no therapeutic effect. 
 
14.1  Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a favourable 
opinion in writing by an HREC as appropriate.  
The PI is responsible for informing the HREC of any amendment to the Protocol in accordance with 
local requirements. In addition, the HREC must approve all advertising used to recruit participants for 
the study. The protocol must be re-approved by the HREC upon receipt of amendments and annually, 
as local regulations require. 
The PI is also responsible for providing the HREC with reports of any reportable serious adverse drug 
reactions from any other study conducted with the study drug (active).  
Progress reports and notifications of serious adverse drug reactions will be provided to the HREC 
according to local regulations and guidelines. 
 
 
15.0 REPORTING of SERIOUS ADVERSE EVENTS and BLEEDING EVENTS 
 
All SAEs or bleeding events Grade 3+ should be emailed to:  
Prof Anders Aneman anders.aneman@health.nsw.gov.au   
AND  
Dr Lucy Coupland l.coupland@unsw.edu.au within 24 hr of occurrence.  
 
Definition of Serious Adverse Events 
As eligible patients are critically-ill and requiring admission to Intensive Care, their condition prior to 
entering the study is already a serious event.  Reporting of serious adverse events that occur in study 
participants will, therefore, be serious adverse events that are considered unrelated to underlying 
disease progression in the opinion of the Investigator. 
 
 
15.1 
Reporting of bleeding events 

 
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As bleeding is the most likely side-effect of alteplase treatment, ALL bleeding events Grade 3 or greater 
according the CTCAE (version 5.0) grading system, will be reported as an SAE irrespective of whether 
it is considered related to study-treatment or not.  
 
Grade 1 events, those not requiring medical intervention, will not be reported as critically-ill patients 
have multiple intravenous/arterial access devices that ooze small amounts of blood at the insertion 
sites. Grade 2 events will be reported as an Adverse Event. 
 
 
Grade 1  
Minor bleeding, intervention not indicated – will not be reported 
Grade 2  
Moderate bleeding, intervention indicated 
Grade 3 
Transfusion indicated, invasive intervention indicated 
Grade 4 
Life-threatening consequences, urgent intervention indicated 
Grade 5 
Death 
 
 
16.0 STUDY OVERSIGHT and INDEPENDENT MONITORING 
The Study Committee, consisting of the Investigator Team, will meet upon the occurrence of all SAEs 
and Grade 3+ bleeding events; at the completion of each patient group on Stage 1; on a monthly basis; 
and following the interim analyses to review study progress and results.  
 
An Independent Safety and Data Monitoring Committee (ISDMC) will also be established to oversee 
the study conduct. The ISDMC will consist of an Intensive Care Specialist, a Haematologist familiar 
with ClotPro and VET, a Respiratory Physician and a Senior Biostatistician. The ISDMC will be notified 
of all SAEs and Grade 3+ bleeding events within 24 hr of occurrence, and provided with a report 
following each of the 4 patient groups on Stage 1, and the interim analysis on Stage 2. The ISDMC will 
be responsible for determining whether it is safe and ethical for the study to continue, or whether the 
protocol requires amending following the occurrence of SAEs and bleeding events, and following each 
of the key study progress points. In Stage 1 of the study, recruitment to the next Patient Group will 
not occur until the ISDMC has provided approval to do so. 
 
Members of the ISDMC are: Prof Anthony Delaney (Intensivist), Royal North Shore Hospital, Sydney 
University; Prof Christine Jenkins (Respiratory Physician), Concorde Hospital, The George Institute for 
Global Health; A/Prof Elizabeth Holliday (Medical Statistician), School of Medicine and Public Health, 
Newcastle University; Dr Philip Crispin (Haematologist), The Canberrra Hospital, Australian National 
University 
 
17.0 STUDY PROCEDURE BENEFITS 
There are significant potential benefits to participants enrolled on this study including the 
preservation of organ function and the avoidance of significant morbidity or death due to ARDS. 
 
 
18.0 STUDY PROCEDURE RISKS   
The risks associated with this study is the potential for bleeding complications associated with 
alteplase treatment. Bleeding may be mild, moderate or severe. This risk is being moderated through 
screening of participant risk prior to study enrolment, and by frequent VET monitoring throughout 
alteplase treatment. The volume of the alteplase infusion will be minimised to prevent fluid overload. 
 

 
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The amount of blood required for VET testing is minimal – 2.7 mL each time. This volume of blood at 
the frequency it is being collected will not impact upon an adult. 
 
No other procedures are being conducted for the purposes of this study. 
 
 
19.0 CONFIDENTIALITY & PRIVACY 
 
19.1 
Data Collection and Storage 
Participants will be assigned a unique study number upon enrolment that will be used on all study 
documentation. A participant log will be maintained within the ICU Clinical Trials Unit of the Liverpool, 
Bankstown and Campbelltown Hospitals in a locked office so that re-identification can occur if 
required. Data provided to the Study Committee and the ISDMC will be de-identified but re-
identifiable if required. 
 
A RedCAP database will be established for the study and eCRFs designed to capture the de-identified 
demographic, disease severity, clinical, pathology and VET data that will be collected. The data will be 
backed up regularly, and 2 copies kept by the Principal Investigators (Aneman and Coupland), and 
accessible only by the Principal Investigators and Study Coordinators through password access. 
 
19.2  Retention of Records 
All source data, clinical records and laboratory data relating to the study will be archived for 15 years 
after the completion of the study. All data will be available for retrospective review or audit. 
Source documents are original documents, data, and records from which the subject’s eCRF data are 
obtained. These include, but are not limited to: hospital records, clinical and office charts, laboratory 
and pharmacy records, diaries, microfiches, radiographs, angiograms, study drug accountability logs, 
and correspondence.  
The Investigator and study staff are responsible for maintaining a comprehensive filing system of all 
study-related (essential) documentation. These include, but are not limited to: HREC correspondence, 
study drug accountability logs, and curricula vitae of all personnel participating in the study. These 
files must be suitable for inspection at any time by the Sponsor, monitor, and/or applicable regulatory 
authorities. All essential documentation should be retained by the institution for 15 years (as required 
in Australia). 
No study document should be destroyed without prior written agreement between the Sponsor and 
the Investigator. If the Investigator wishes to assign the study records to another party or move them 
to another location, the PI must notify the Sponsor in writing of the new responsible person and/or 
the new location. 
 
19.3  Disclosure and Confidentiality 
The Investigator agrees to keep all information provided by the Sponsors in strict confidence and to 
request similar confidentiality from site staff and the local HREC. Study documents will be stored 
appropriately to ensure their confidentiality. The information provided by the Sponsors to the 
Investigator may not be disclosed to others without direct written authorization from the Sponsors, 
except to the extent necessary to obtain informed consent from participants who wish to participate 
in the study. 

 
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The Investigator must ensure that the participants anonymity is also maintained. Participants should 
only be identified by their initials and a study number on the eCRFs and other source documents. 
Other study-related documents (e.g., signed ICFs) should be kept in strict confidence by the 
Investigator. 
 
 
 
20.0 STUDY TERMINATION 
The study will be terminated should cumulative evidence indicate that alteplase treatment is 
detrimental. This decision will be made by the ISDMC.   
 
Alternatively, should cumulative evidence suggest there is significant benefit to alteplase treatment, 
the study will be terminated, analysed and published as soon as possible. Again this decision will be 
made by the ISDMC. 
 
 
21.0 FUNDING 
A ClotPro machine has been donated to the Liverpool Hospital Intensive Care Unit for the purposes of 
this study by Haemoview Diagnostics Australia. Grant funds have been obtained to cover the purchase 
of a ClotPro machine, reagents and disposables for Bankstown Hospital ICU. The outcome of an 
additional grant application for the purchase of a ClotPro machine, reagent and consumables for 
Campbelltown Hospital ICU will be known in the near future.  
 
The additional costs of the study at Liverpool Hospital will be covered by the Clinical Research Fund of 
the Liverpool Hospital Intensive Care Unit. 
 
As SWSLHD is the Sponsor of this clinical trial, indemnity is provided by the Trust Management Fund 
as described in PD2011_006 Clinical Trials – Insurance and Indemnity. 
 
22.0 RESEARCH OUTCOMES 
Following the completion of this study, if alteplase treatment is demonstrated to restore fibrinolysis 
the Investigators will collaborate with the REMAP-CAP team at Monash University to undertake a 
larger trial with the power to determine whether improvements in organ function and patient 
outcomes also occur. 
 
A Clinical Study Report will be prepared in accordance with ICH GCP requirements. 
 
The results will be published expeditiously via the REMAP-CAP international network of Intensive Care 
clinicians, in a peer-reviewed international medical journal, and presented at medical meetings and 
conferences.  If beneficial, it may also attract the attention of the media in which case a summary of 
the results would be provided in lay terms. 
 
23.0  QUALITY CONTROL AND ASSURANCE 
23.1  Compliance with Regulations 
This study is being conducted under the TGA Clinical Trial Notification (CTN) Scheme  
The study will be carried out in accordance with the current version of the Declaration of Helsinki 
(Ethical Principles for Medical Research Involving Human Subjects), and with the NHMRC National 

 
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Statement on Ethical Conduct in Human Research 2007 (updated 2018). The conduct of the study will 
be in accordance with the Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice 
ICH E6 (R2), annotated with comments by the Australian Therapeutic Goods Administration (TGA; June 
2018). 
24.0  SPONSOR AND INVESTIGATOR OBLIGATIONS 
 
24.1  Protocol Amendments 
Neither the Investigator nor the Sponsors will modify or alter this protocol without the agreement of 
the other. All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol amendments 
will be submitted to the relevant institutional HREC for approval before implementation, as required 
by local regulations. The only exception will be when the amendment is necessary to eliminate an 
immediate hazard to the trial participants. In this case, the necessary action will be taken first, with 
the relevant protocol amendment following shortly thereafter. 
24.2  Protocol Deviations 
Should any protocol deviation occur, they must be reported to the Sponsor as soon as is reasonably 
practical. The deviation and the reason for its occurrence must be documented, reported to the 
relevant HREC (if required) and included in the CSR. 
 
  
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VETtiPAT ARF 
Final Protocol: Version 4.1 dated 1 Sept 2022 
 
Page 24 of 24 
 
26.0  Appendix 1: Anticoagulant and Platelet-Antagonists 
 
Continued treatment with the following drugs, or others with similar actions, render the patient 
ineligible for this study: 
 
Abciximab 
Apixaban 
Aspirin 
Aspirin + Clopidogrel 
Clopidogrel 
Dabigatran 
Eptifibatide 
Non-steroidal anti-inflammatory drugs (NSAIDS) 
Persantin 
Rivaroxaban 
Ticagrelor 
Tirofiban 
Warfarin