Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000169640
Ethics application status
Approved
Date submitted
1/02/2023
Date registered
17/02/2023
Date last updated
17/02/2023
Date data sharing statement initially provided
17/02/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
An evaluation of the blood thinning effects of the medications Alteplase and Dornase in the management of adults with complex pleural infections.
Scientific title
Systemic Fibrinolytic Activity of Intrapleural Alteplase in Pleural Infection
Secondary ID [1] 308802 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pleural infection 328754 0
Condition category
Condition code
Respiratory 325757 325757 0 0
Other respiratory disorders / diseases
Blood 325758 325758 0 0
Clotting disorders
Infection 326014 326014 0 0
Other infectious diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Pleural infection is associated with significant mortality and morbidity. Historically, pleural infections have been managed with surgical methods. However, intrapleural instillation of tissue-plasminogen activator (tPA) and deoxyribonuclease (DNAse), have been shown to be effective and safe. There remain unanswered questions about intrapleural tPa, in particular the systemic fibrinolytic effects.
This study seeks to measure systemic markers of coagulation and fibrinolysis in people receiving intrapleural therapy at current standard doses.

The study will recruit participants (n=50) who are deemed suitable by their treating physician as having a complex pleural infection requiring the instillation of tPa and DNAse.
Prior to receiving intrapleural fibrinolytics agents, all patients receive assessment of coagulation factors as they would in standard practice. At this same episode of venepuncture additional serum samples will be sent:
Plasminogen activator inhibitor-1 (PAi1) - naturally occurring serine kinase inhibitor that acts as the main inhibitor of tPA
Overall haemostatic potential assay (OHP) - measurement of fibrin generation, which represents the interactions between prothrombotic and thrombolytic agents in the serum at the time of collection
Plasminogen - target for tPA, which cleaves plasminogen into plasmin which binds to and degrades fibrin (ie. thromboses)
Tissue Plasminogen Activator (tPA) - measurement if there is systemic spread of tPa from the pleural space

The study will collect serum coagulation data following administration of intrapleural tPA and DNAse on up to three consecutive days. The timing and dosage of which will be decided upon by their treating physician in line with standard practice. The participant will undergo repeat venepuncture 45 minutes post instillation to assess coagulation status as well as the experimental serum tests listed above. It is worth noting that the patient would routinely undergo venepuncture on these days as part of standard care, and such the venepuncture does not amount to a large change from usual practice.
Observations of participants will be in the inpatient hospital setting. Observation will begin the day prior to receiving their first dose of intrapleural fibrinolytic agents and cease after the final dose (up to four consecutive days).
Intervention code [1] 325252 0
Early Detection / Screening
Comparator / control treatment
The study is designed so that all participants can act as their own controls.
Each participant will receive the same testing prior to and following each instillation of intrapleural fibrinolytic agents. This design enables a controlled comparison between the serum coagulation status of a patient with complex pleural infection without intrapleural tPA, and then the same patient following tPA instillation,
Control group
Active

Outcomes
Primary outcome [1] 333606 0
Change in serum coagulation assays following the administration of intrapleural tPA. Specifically change in International Normalised Ratio (INR),
Timepoint [1] 333606 0
45 minutes following first dose of intrapleural tPA
45 minutes following second dose of intrapleural tPA
45 minutes following third (final) of intrapleural tPA
Primary outcome [2] 333869 0
Change in serum coagulation assays following the administration of intrapleural tPA.
Specifically change in Activated Partial Thromboplastin Time (APTT)
Timepoint [2] 333869 0
45 minutes following first dose of intrapleural tPA
45 minutes following second dose of intrapleural tPA
45 minutes following third (final) of intrapleural tPA
Primary outcome [3] 333870 0
Change in serum coagulation assays following the administration of intrapleural tPA.
Specifically change in fibrinogen.
Timepoint [3] 333870 0
45 minutes following first dose of intrapleural tPA
45 minutes following second dose of intrapleural tPA
45 minutes following third (final) of intrapleural tPA
Secondary outcome [1] 417730 0
Change in novel serum assays following the administration of intrapleural tPA. Specifically change in overall haemostatic potential.
Timepoint [1] 417730 0
45 minutes following first dose of intrapleural tPA
45 minutes following second dose of intrapleural tPA
45 minutes following third (final) of intrapleural tPA
Secondary outcome [2] 418582 0
**Please Note: This is a primary outcome**
Change in serum coagulation assays following the administration of intrapleural tPA. Specifically change in d-dimer.
Timepoint [2] 418582 0
45 minutes following first dose of intrapleural tPA
45 minutes following second dose of intrapleural tPA
45 minutes following third (final) of intrapleural tPA
Secondary outcome [3] 418583 0
Change in novel serum assays following the administration of intrapleural tPA. Specifically change in Plasminogen Activator Inhibitor-1(PAi1).
Timepoint [3] 418583 0
45 minutes following first dose of intrapleural tPA
45 minutes following second dose of intrapleural tPA
45 minutes following third (final) of intrapleural tPA
Secondary outcome [4] 418584 0
Change in novel serum assays following the administration of intrapleural tPA. Specifically change in plasminogen.
Timepoint [4] 418584 0
45 minutes following first dose of intrapleural tPA
45 minutes following second dose of intrapleural tPA
45 minutes following third (final) of intrapleural tPA
Secondary outcome [5] 418585 0
Change in novel serum assays following the administration of intrapleural tPA. Specifically change in serum tPA.
Timepoint [5] 418585 0
45 minutes following first dose of intrapleural tPA
45 minutes following second dose of intrapleural tPA
45 minutes following third (final) of intrapleural tPA

Eligibility
Key inclusion criteria
Adult patients (18 years and older) with complex pleural infections requiring intrapleural tPA and DNAse as decided by their treating physician.
Complex pleural infection are those infections that do not resolve/drain with antibiotics and thorocostomy tube that may have a loculated/septated appearance on imaging, may have a purulent macroscopic appearance and may have cultured bacteria from pleural fluid.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Individuals that are deemed unsuitable for intrapleural tPA. These include those with active bleeding, current use of an anticoagulant with evidence of affected coagulation status, a medical condition which results in an affected coagulation status or those that are pregnant.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
This is a pilot study to evaluate if there are any changes in conventional coagulation markers and global fibrinolytic assays as well as more experimental assays following the administration of a standard dose of intra-pleural tPA in patients with pleural infection. There is little published data and hence a formal power calculation is difficult. As part of a pilot study we propose recruiting a maximum of 50 patients in total. This sample size will provide an ability to test for a difference/change in the paired observations of approximately 75% of the standard deviation of the difference (i.e. if standard deviation of difference is equal to 1, a sample size of n=16 will able to detect a difference of 0.75 in paired means).

Methodology:
For comparisons between groups t-test will be used for normally distributed continuous variable, Mann-Whitney (rank-sum) test for skewed continuous variables and Chi-square test for categorical variables. Given the sample size, the paired observation for each primary outcome measure is likely to be normally distributed, thus a paired t-test will be used to test for differences between baseline and post administration of intrapleural tPA. If possible, associations with baseline factors for the continuous outcome measures will be analysed using generalised linear models.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
13/03/2023
Actual
Date of last participant enrolment
Anticipated
4/12/2023
Actual
Date of last data collection
Anticipated
15/12/2023
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23858 0
The Northern Hospital - Epping
Recruitment postcode(s) [1] 39317 0
3076 - Epping

Funding & Sponsors
Funding source category [1] 313019 0
Hospital
Name [1] 313019 0
Northern Health
Country [1] 313019 0
Australia
Primary sponsor type
Hospital
Name
Northern Health
Address
185 Cooper Street, Epping, Victoria, 3076
Country
Australia
Secondary sponsor category [1] 314707 0
None
Name [1] 314707 0
Address [1] 314707 0
Country [1] 314707 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312280 0
Austin Health Human Reasearch Ethics Committee
Ethics committee address [1] 312280 0
145 Studley Rd, Heidelberg, Victoria, 3084
Ethics committee country [1] 312280 0
Australia
Date submitted for ethics approval [1] 312280 0
26/02/2021
Approval date [1] 312280 0
26/08/2021
Ethics approval number [1] 312280 0
HREC/64872

Summary
Brief summary
Introduction:
You are invited to take part in this research project, Systemic fibrinolytic Activity of Intrapleural Alteplase in Pleural Infection. This is because you have a pleural infection (which means that fluid has collected around the lung and is infected) and you are to have Intrapleural Alteplase as part of your standard of care. The research project is aiming to test if a common treatment for pleural infection (Alteplase), will enter the bloodstream and circulate around the body after it is given into the pleural fluid.

Purpose:
The lung and the inside of the chest wall are both covered by a thin lining called the pleura. Under normal circumstances, this lining produces a very small amount of fluid to lubricate the lung during breathing. Sometimes there can be a build-up of fluid in the space between the pleural linings which gets infected, which is called a pleural infection. These occur in up to 50% of people who have pneumonia (infection of the lung), but are often very small and can’t be seen on a chest x-ray. In many cases, they clear up with antibiotics; less commonly, a chest tube is required to drain the fluid. Sometimes chest drainage is not enough to clear the fluid as a mesh of protein locks away the infected fluid in pockets which the chest tube may not reach. When these protein-pockets happen, people are said to have a complex pleural effusion. To help break down these protein-pockets, sometimes a medication called Alteplase is given through the chest tube.
Alteplase has been proven to help people with pleural infection that also have complex pleural effusions, to get better and avoid surgery. It doesn’t appear to be absorbed into the body when given into the pleural space but this hasn’t been proven. We are doing this project to see if this is true or not. It is important to know if Alteplase given into the pleural space enters the blood-stream as it can cause bleeding in other parts of the body if this happens.

What does participation involve:
There is a list of criteria that must be met in order to participate in the study. The study team believe you meet the study criteria and that is why you have been approached about it. If you agree to the study, you will be participating in a prospective study. You will have 1 additional blood tests per dose of Alteplase compared to normal treatment, taking about 20mls of blood from your veins each time. This will be done 45 minutes after receiving Alteplase. The blood will be taken either by a lung specialist or a specialist nurse. If it is anticipated that there will be difficulty taking these blood sample, a lung specialist will acquire the blood with the help of an ultrasound machine.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124094 0
Dr Sanjeevan Muruganandan
Address 124094 0
Northern Health 185 Cooper St Epping 3076 Victoria
Country 124094 0
Australia
Phone 124094 0
+61 0422307098
Fax 124094 0
Email 124094 0
sanjeevan.muruganandan@nh.org.au
Contact person for public queries
Name 124095 0
Dr Sanjeevan Muruganandan
Address 124095 0
Northern Health 185 Cooper St Epping 3076 Victoria
Country 124095 0
Australia
Phone 124095 0
+61 0422307098
Fax 124095 0
Email 124095 0
sanjeevan.muruganandan@nh.org.au
Contact person for scientific queries
Name 124096 0
Dr Sanjeevan Muruganandan
Address 124096 0
Northern Health 185 Cooper St Epping 3076 Victoria
Country 124096 0
Australia
Phone 124096 0
+61 0422307098
Fax 124096 0
Email 124096 0
sanjeevan.muruganandan@nh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.