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Trial registered on ANZCTR


Registration number
ACTRN12622001427763
Ethics application status
Approved
Date submitted
1/11/2022
Date registered
8/11/2022
Date last updated
8/11/2022
Date data sharing statement initially provided
8/11/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The effects of dual anti-platelet therapy (DAPT) on neutrophil and platelet activation
Scientific title
A Study to Evaluate the Effects of Dual Anti-Platelet Therapy on the Platelet-Neutrophil Interaction in Healthy Adults
Secondary ID [1] 308152 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Coronary artery disease 327876 0
Condition category
Condition code
Inflammatory and Immune System 324960 324960 0 0
Other inflammatory or immune system disorders
Cardiovascular 324961 324961 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There are two arms to this study, the treatment intervention arm and the treatment-naive arm. Healthy individuals in the intervention arm will receive dual antiplatelet therapy for two days in oral tablet form, a combination of aspirin (300mg loading dose on day 1, 100mg maintenance dose on day 2, 24 hours post loading dose) and ticagrelor (180mg loading dose on day 1, 90mg maintenance dose on day 1, 8-hours post loading dose, 90mg maintenance dose on day 2, 24 hours post loading dose). Drug adherence is monitored by verbal confirmation only. This mimics the routine of DAPT administration given to individuals with acute myocardial infarction (AMI) in hospital in Aotearoa New Zealand.

20 participants are allocated to this treatment intervention arm after we have enrolled 3 participants into the treatment naive arm.
Intervention code [1] 324603 0
Treatment: Drugs
Comparator / control treatment
Participants in the treatment-naive arm are the control group. These participants do not receive any intervention. Blood is drawn from these participants and neutrophils are isolated and co-cultured with platelets received from participants in the treatment intervention arm. These participants will give blood for a total of 20 times maximum.
Control group
Active

Outcomes
Primary outcome [1] 332760 0
We isolate neutrophils from blood samples, stimulate these in the presence and absence of platelets and measure a change in Myeloperoxidase activity which we will assess by performing the Myeloperoxidase assay. This assay measures myeloperoxidase activity through a colorimetric assay and absorbance readings of the colorimetric change represent changes in activity.
Timepoint [1] 332760 0
immediately prior to receiving the first dose of DAPT (pre treatment intervention) and post-treatment, immediately after receiving the final dose of DAPT on day 2
Primary outcome [2] 332761 0
We isolate platelets from blood samples, stimulate these in the presence and absence of neutrophils and measure their aggregation through changes in light transmission aggregometry which is a light absorbance based assay.
Timepoint [2] 332761 0
immediately prior to receiving the first dose of DAPT (pre treatment intervention) and post-treatment, immediately after receiving the final dose of DAPT on day 2
Primary outcome [3] 332762 0
We isolate neutrophils and platelets from blood samples and stimulate these in co-culture or individually and changes in ELISA intensity for NET specific markers (Myeloperoxidase-DNA, neutrophil-elastase-DNA, and H3-citrullinated histone complexes) will be assessed.
Timepoint [3] 332762 0
immediately prior to receiving the first dose of DAPT (pre treatment intervention) and post-treatment, immediately after receiving the final dose of DAPT on day 2
Secondary outcome [1] 414643 0
Nil
Timepoint [1] 414643 0
Nil

Eligibility
Key inclusion criteria
for the intervention arm: healthy volunteers that are aged between 45 and 70 years
for the treatment-naive arm: healthy volunteers that are aged between 18 and 70 years
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
•known cardiovascular or inflammatory disease,
•known disorder associated with platelet dysfunction or bleeding,
•participant is pregnant
•participant has Type II diabetes
•participant has history of adverse drug reaction
•participant has been treated with cardiovascular and/or immune-modulating drugs and/or antiplatelet agents within 7 days prior to recruitment

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
participants in the treatment intervention arm will receive DAPT over the course of 2 days whereas participants in the treatment-naiive arm will not receive any DAPT.
Phase
Phase 2
Type of endpoint/s
Pharmacodynamics
Statistical methods / analysis
With a sample size of 10 individuals in the intervention arm, we have the power to detect a 10% difference in platelet aggregation between healthy subjects with and without DAPT treatment with 85% power and 5% significance. These calculations were based on the mean (µ=93.67%) and standard deviation (s=6.413%) of n=21 measurements of platelet aggregation from healthy individuals in response to 1000nM Arachidonic Acid (AA).
With a sample size of 10 individuals in the intervention arm, we have the power to detect a 28% difference in relative Myeloperoxidase (MPO) signal between healthy subjects with and without DAPT treatment with 85% power and 5% significance. These calculations were based on the mean (µ=5.85 signal:noise) and standard deviation (s=0.89 signal:noise) of n=6 measurements of normalized MPO absorbance values from healthy individuals in response to 500nM Phorbol-12-myristate-13-acetate (PMA).

Data will be analyzed using Graphpad Prism software.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
16/01/2023
Actual
Date of last participant enrolment
Anticipated
1/01/2024
Actual
Date of last data collection
Anticipated
1/03/2024
Actual
Sample size
Target
23
Accrual to date
Final
Recruitment outside Australia
Country [1] 25054 0
New Zealand
State/province [1] 25054 0
Wellington

Funding & Sponsors
Funding source category [1] 312415 0
University
Name [1] 312415 0
University of Otago
Country [1] 312415 0
New Zealand
Primary sponsor type
Individual
Name
Dr. Kathryn Hally
Address
Dr. Kathryn Hally, University of Otago, 23a Mein Street, 6021 Newtown, Wellington, New Zealand
Country
New Zealand
Secondary sponsor category [1] 313985 0
Individual
Name [1] 313985 0
Sonja Hummel
Address [1] 313985 0
Sonja Hummel, University of Otago, 23a Mein Street, 6021 Newtown, Wellington, New Zealand
Country [1] 313985 0
New Zealand
Other collaborator category [1] 282448 0
Individual
Name [1] 282448 0
Associate Professor Peter Larsen
Address [1] 282448 0
Associate Professor Peter Larsen, University of Otago, 23a Mein Street, 6021 Newtown, Wellington, New Zealand
Country [1] 282448 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311761 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 311761 0
Central Health and Disability Ethics Committee
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 311761 0
New Zealand
Date submitted for ethics approval [1] 311761 0
Approval date [1] 311761 0
27/09/2022
Ethics approval number [1] 311761 0
2022 EXP 12091

Summary
Brief summary
Aspirin and ticagrelor are anti-platelet medications given to people suffering from a heart attack. This type of medication prevents platelets from becoming activated. Platelets repair damage in blood vessels. However, these cells also cause blood clots in the arteries of the heart, and this can cause a heart attack.
Neutrophils are another cell type that is crucial for our health. Neutrophils are part of our immune system and survey the blood for any intruding pathogens. These cells ‘activate’ and become inflammatory when our body encounters an infection. However, these cells have been shown to participate in heart attacks also. These cells can produce a very inflammatory substance called Neutrophil Extracellular Traps (NETs) in a process called NETosis. NETs are great during infection, as they trap invading pathogens. However, these NETs can also activate platelets, a process which we know can cause a heart attack. We believe that anti-platelet medication (aspirin and ticagrelor) will reduce the ability of neutrophils to produce NETs and will reduce the ability of platelets to activate in response to NETs. It could be beneficial for anti-platelet medication to have this effect, as this may reduce inflammation after a heart attack.

We aim to:
• We aim to investigate whether anti-platelet medication affects neutrophils and their ability to undergo NETosis.
• We also aim to investigate whether anti-platelet medication affects the ability of platelets to activate in response to NETs.
There are two "arms" of this study:
1. The intervention arm: we are recruiting 20 volunteers to take anti-platelet medication.
2. The treatment-naïve arm: we are recruiting 3 volunteers to be a control for the intervention arm. Recruitment into this arm does not involve taking anti-platelet medication.

At the first study visit, we will take a “baseline” blood test. After we have taken the “baseline” blood test, participants will be asked to take their first dose of anti-platelet medication. These are aspirin and ticagrelor. In between the First and Second study visit, participants will be asked to take their second dose of anti-platelet medication in the evening of the first study visit. The second study visit will occur the day after the first study visit. On this day, participants will take the third and final dose of anti-platelet medications in the morning, prior to the second study visit. At the second study visit, we will take a second blood sample, no later than 6 hours after participants have taken their third dose of anti-platelet medications.
Three healthy volunteers in the treatment naiive-arm will give blood for each of the participants in the treatment-intervention arm to provide neutrophils that have not been influenced by DAPT.
A study researcher will then assess the extend to which neutrophils can produce NETs in the presence of platelets pre- and post treatment with DAPT.
Trial website
Trial related presentations / publications
Public notes
•participant is awaiting a COVID-19 test result at time of recruitment or at any point throughout the study will be excluded from the study
•participant has or had acute illness (including COVID-19) within 6 weeks prior to recruitment will be excluded from the study

Contacts
Principal investigator
Name 122274 0
Dr Kathryn Hally
Address 122274 0

The University of Otago, Wellington
Department of Surgery and Anaesthesia
23A Mein Street, Newtown
Wellington 6021
Country 122274 0
New Zealand
Phone 122274 0
+64 4 27 636 0914
Fax 122274 0
Email 122274 0
[email protected]
Contact person for public queries
Name 122275 0
Kathryn Hally
Address 122275 0

The University of Otago, Wellington
Department of Surgery and Anaesthesia
23A Mein Street, Newtown
Wellington 6021
Country 122275 0
New Zealand
Phone 122275 0
+64 4 27 636 0914
Fax 122275 0
Email 122275 0
[email protected]
Contact person for scientific queries
Name 122276 0
Kathryn Hally
Address 122276 0

The University of Otago, Wellington
Department of Surgery and Anaesthesia
23A Mein Street, Newtown
Wellington 6021
Country 122276 0
New Zealand
Phone 122276 0
+64 4 27 636 0914
Fax 122276 0
Email 122276 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
individual participant data underlying published results in raw format
When will data be available (start and end dates)?
beginning 3 months and ending 2 years following main results publication
Available to whom?
De-identified data may be included in published study results including, but not limited to, peer-reviewed publications, clinical trial registry websites, scientific meetings, and regulatory/marketing submissions, decided on a case-by-case basis by primary study investigator
Available for what types of analyses?
analyses that aid the future pathway of care of patients suffering from coronary artery diseases
How or where can data be obtained?
access subject to approvals by Principal Investigator ([email protected])


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17326Study protocol    384804-(Uploaded-11-10-2022-12-22-34)-Study-related document.docx
17327Ethical approval    384804-(Uploaded-11-10-2022-12-22-57)-Study-related document.pdf
17328Informed consent form    384804-(Uploaded-11-10-2022-12-23-15)-Study-related document.doc



Results publications and other study-related documents

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