ANZCTR - Registration

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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]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Coronary artery disease

Condition category

Condition code

Inflammatory and Immune System

Other inflammatory or immune system disorders

Cardiovascular

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]

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]

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]

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]

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]

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]

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]

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]

Nil

Timepoint [1]

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

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Wellington

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Otago

Address [1]

23a Mein Street, 6021 Newtown, Wellington, New Zealand

Country [1]

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]

Individual

Name [1]

Sonja Hummel

Address [1]

Sonja Hummel, University of Otago, 23a Mein Street, 6021 Newtown, Wellington, New Zealand

Country [1]

New Zealand

Other collaborator category [1]

Individual

Name [1]

Associate Professor Peter Larsen

Address [1]

Associate Professor Peter Larsen, University of Otago, 23a Mein Street, 6021 Newtown, Wellington, New Zealand

Country [1]

New Zealand

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Health and Disability Ethics Committee

Ethics committee address [1]

Central Health and Disability Ethics Committee
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

Approval date [1]

27/09/2022

Ethics approval number [1]

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

Dr Kathryn Hally

Address

The University of Otago, Wellington
Department of Surgery and Anaesthesia
23A Mein Street, Newtown
Wellington 6021

Country

New Zealand

Phone

+64 4 27 636 0914

Fax

Kathryn.Hally@otago.ac.nz

Contact person for public queries

Name

Kathryn Hally

Address

The University of Otago, Wellington
Department of Surgery and Anaesthesia
23A Mein Street, Newtown
Wellington 6021

Country

New Zealand

Phone

+64 4 27 636 0914

Fax

Kathryn.Hally@otago.ac.nz

Contact person for scientific queries

Name

Kathryn Hally

Address

The University of Otago, Wellington
Department of Surgery and Anaesthesia
23A Mein Street, Newtown
Wellington 6021

Country

New Zealand

Phone

+64 4 27 636 0914

Fax

Kathryn.Hally@otago.ac.nz

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 (Sonja.Hummel@postgrad.otago.ac.nz)

What supporting documents are/will be available?

Doc. No.	Type	Attachment
17326	Study protocol	384804-(Uploaded-11-10-2022-12-22-34)-Study-related document.docx
17327	Ethical approval	384804-(Uploaded-11-10-2022-12-22-57)-Study-related document.pdf
17328	Informed 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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No additional documents have been identified.

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