The pharmacogenetics of aspirin resistance

ISRCTN	ISRCTN71079188
DOI	https://doi.org/10.1186/ISRCTN71079188
Protocol serial number	RGHT000270
Sponsor	Royal Group of Hospitals Trust (UK)
Funders	Royal Hospitals Trust Clinical Fellowship (UK), Northern Ireland Chest Heart & Stroke Association (UK)

Submission date: 06/10/2006
Registration date: 14/03/2007
Last edited: 15/04/2016

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Injury, Occupational Diseases, Poisoning

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr Pascal McKeown
Scientific

Consultant/Senior Lecture in Cardiology
Royal Hospitals Trust
West Wing, First Floor
Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Phone	+44 28 906 32519
Email	p.p.mckeown@qub.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised repeated period crossover trial design
Secondary study design	Randomised cross over trial
Scientific title	The pharmacogenetics of aspirin resistance
Study objectives	The Antiplatelet Trialists' Collaboration meta-analyses (1994) documented a 25% reduction of death, myocardial infarction, and stroke in high-risk patients treated with aspirin. However, some patients continue to experience clinical events despite aspirin therapy, indicating that the anti-platelet effect of aspirin may not be uniform in all patients. Clinical aspirin resistance refers to those patients who have recurrent thrombotic events despite compliance with therapy. Biochemical aspirin refers to inadequate platelet inhibition on formal testing. The aims of this proposed study are to use a repeated period crossover trial design in order to assess the reproducibility of aspirin resistance in healthy control individuals, using standard optical platelet aggregometry. Additional measures of platelet function will also be assessed using the Platelet Function Analyser (PFA-100) system, and levels of serum thromboxane B2 and urinary 11-dehydro thromboxane B2. Furthermore, the contribution of genetic polymorphisms in candidate genes to the phenomenon of aspirin resistance will be characterised. Polymorphisms of several contributing genes including the Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), GlycoProtein IIIa (GPIIIA), and adenosine 5-diphosphate receptor genes will be investigated using standard molecular approaches. 01/10/2012: Please note that the anticipated end date of this trial was updated from 01/08/2009 to 30/08/2012
Ethics approval(s)	Approval received from the Office for Research Ethics Committees Northern Ireland (ORECNI) on the 14th June 2006 (reference number: 06/NIR01/44).
Health condition(s) or problem(s) studied	Aspirin resistance
Intervention	The study is a repeated crossover trial design of two treatments and four periods. The aspirin dose will be either 75 mg or 300 mg but will be fixed within individual patients. A subject will be randomised to one of four treatment sequences: ABBA, BAAB, ABAB or BABA, where A is active drug and B is placebo. Each individual study period will last for three weeks, therefore the total period of study for each patient will be 12 weeks. This type of design allows the study of treatment, subject, period and carry-over effects, and their interactions, specifically the subject-by-treatment interaction. The individuals will be seen at baseline and once informed consent has been obtained, baseline tests for platelet function tests (optical aggregometry, PFA-100) and serum/urine thromboxane levels will be taken, as will whole blood for later analysis of genetic polymorphisms. Further samples for platelet function testing will be taken at the end of each crossover period.
Intervention type	Drug
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Aspirin
Primary outcome measure(s)	1. Assess the reproducibility of aspirin resistance in healthy control individuals, as defined by standard optical platelet aggregometry 2. Characterise the contribution of genetic polymorphisms in candidate genes, specifically the cyclooxygenase and adenosine 5-diphosphate receptor genes, to the phenomenon of aspirin resistance
Key secondary outcome measure(s)	1. The assessment of the reproducibility of aspirin response as defined by other platelet function tests (PFA-100 system, thromboxane levels) 2. The contribution of other genetic polymorphisms to the phenomenon of aspirin resistance 3. The correlation between the various platelet function tests used in this study
Completion date	30/08/2012

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Upper age limit	60 Years
Sex	Not Specified
Target sample size at registration	150
Key inclusion criteria	Healthy individuals aged between 18 to 60 years
Key exclusion criteria	Current exclusion criteria as of 01/10/2012 1. Use of other anti-platelet drugs (thienopyridines, GPIIb/IIIa antagonists, dipyridamole) because these drugs would interfere with platelet function assays 2. Use of other non-steroidal anti-inflammatory drugs, because of the pharmacodynamic interactions 3. History of dyspepsia or peptic ulceration requiring treatment with proton pump inhibitors/H2 antagonists, in view of the increased risk of gastrointestinal haemorrhage 4. History of systemic inflammatory diseases, in view of the need for these patients to take anti-inflammatory drugs 5. History of asthma 6. Use of other aspirin-containing medications (including herbal preparations) 7. Family or personal history of bleeding disorders 8. Use of oral anticoagulants 9. Platelet count outside the normal range (150,000 to 450,000/ml) 10. Significant anaemia (Haemoglobin [Hb] less than 10 g/dl) 11. Recent major surgery 12. Known significant malignant disease 13. known aspirin allergy 14.1 Pregnancy 14.2 Women of childbearing potential except in the following circumstances for the duration of the trial: 'monogamous relationship and partner sterilised' or 'for personal reasons not sexually active' or 'use of double barrier methods of contraception' 15. History of lactose intolerance, as lactose if the primary substance contained in the placebo 16. History of gout, as aspirin can precipitate gout 17. History of severe renal or hepatic dysfunction 18. Planned surgery during participation in trial 19. Excessive alcohol ingestion (more than 40 units per week) 20. Inability to provide informed consent Previous exclusion criteria until 01/10/2012: 14. Pregnancy/women of childbearing potential
Date of first enrolment	01/08/2006
Date of final enrolment	30/08/2012

Locations

Countries of recruitment

United Kingdom
Northern Ireland

Study participating centre

Consultant/Senior Lecture in Cardiology

Belfast
BT12 6BA
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Editorial Notes

15/04/2016: No publications found, verifying study status with principal investigator.