E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Heart attack/severe 'unstable' angina |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051592 |
E.1.2 | Term | Acute coronary syndrome |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The principal objective of this study is to assess the effects of two aspirin regimens (very low dose twice daily or standard low dose once daily) on the levels of thromboxane and prostacyclin, substances relevant to platelet activity, measured as their breakdown products in blood and urine, in patients on dual antiplatelet therapy for acute coronary syndromes (heart attacks and severe 'unstable' angina). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to assess the effect of two different regimens of aspirin on platelet function and on bleeding time; and on variability of effect assessed by serum thromboxane and platelet function. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For inclusion in the study, subjects should fulfil the following criteria:
1. Provision of informed consent prior to any study specific procedures
2. Male or female aged greater than 18 years
3. Previous diagnosis of acute coronary syndrome greater than 30 days and less than 10 months before enrolment
4. Receiving dual antiplatelet therapy with aspirin 75 mg once daily and ticagrelor 90 mg twice daily
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E.4 | Principal exclusion criteria |
1. Presence of an indication for dual antiplatelet therapy other than ischaemic heart disease
2. PCI with drug eluting or bare metal stent(s) within 30 days of randomization
3. Any history of stent implantation to the left main coronary artery
4. Any history of stent thrombosis during dual antiplatelet therapy
5. Planned procedure for coronary revascularization
6. Any planned surgery or other procedure that may require suspension or discontinuation of dual antiplatelet therapy expected to occur within 3 months of randomisation
7. Prior intention by patient or physician to discontinue aspirin and/or ticagrelor within the study period
8. Receiving doses of aspirin and ticagrelor other than 75 mg once daily and 90mg twice daily respectively
9. Treatment or planned treatment with antiplatelet medication apart from aspirin or ticagrelor (eg. clopidogrel, prasugrel, dipyridamole, ticlopidine).
10. Current use of a loop, thiazide or potassium sparing diuretic (affects prostanoid assays).
11. Any acute coronary syndrome event within 30 days prior to randomization.
12. Most recent acute coronary syndrome event greater than 10 months prior to randomization.
13. Current or planned use of an oral anticoagulant (e.g. warfarin, dabigatran, rivaroxaban, apixaban) or parenteral anticoagulant (eg. unfractionated heparin, low molecular weight heparin, bivalirudin).
14. Current or planned use of a GPIIb/IIIa inhibitor (eg. abciximab, tirofiban).
15. Current or planned use of a fibrinolytic agent (eg. tissue plasminogen activator).
16. Requiring or likely to require treatment with a non-steroidal anti-inflammatory drug (NSAID), including COX2 inhibitors, and including regular or intermittent/as required use.
17. Receiving a strong inhibitor of CYP3A4 (eg, ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin [but not erythromycin or azithromycin], nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, or over 1 litre daily of grapefruit juice).
18. Receiving simvastatin or lovastatin at doses higher than 40 mg daily.
19. Receiving a CYP3A substrate with a narrow therapeutic index (e.g. cyclosporine or quinidine).
20. Receiving a strong inducer of CYP3A (e.g. rifampin/rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital).
21. History of acute or chronic liver disease (e.g. cirrhosis).
22. End-stage renal failure requiring dialysis.
23. History of alcohol or drug abuse in the last year.
24. Co-morbidity associated with life expectancy less than 1 year.
25. Any other condition deemed by the investigator to affect haemostasis, coagulation, bleeding risk or ability to comply with the study protocol.
26. Females of child-bearing potential unless negative pregnancy test at screening and willing to use effective contraception (i.e. established use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or barrier methods of contraception with spermicide or sole male partner with prior vasectomy and confirmed absence of sperm in ejaculate) for the duration of treatment with study medication.
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E.5 End points |
E.5.1 | Primary end point(s) |
The 3 co-primary outcome measures are:
1. Post-dose serum thromboxane B2, compared within-patients between the 2 dosing regimens by a paired t test. 2. Post-dose urinary PGI-M, compared within-patients between the 2 dosing regimens by a paired t test. 3. Ratio of post-dose serum TXB2:urinary PGI-M, compared within-patients between the 2 dosing regimens by a paired t test.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At 14 days after commencing study medication. |
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E.5.2 | Secondary end point(s) |
1. Pre-dose serum thromboxane B2.
2. Maximum and final post-dose platelet aggregation induced by 0.1, 0.3 and 1 mM arachidonic acid; 1, 4 and 16 µg/ml collagen; and 20 µM ADP.
3. Maximum and final pre-dose platelet aggregation induced by 0.1, 0.3 and 1 mM arachidonic acid; 1, 4 and 16 µg/ml collagen; and 20 µM ADP.
4. Post-dose bleeding time.
5. Ratio of pre-:post-dose serum TXB2.
6. Ratio of pre-:post-dose maximum and final platelet aggregation induced by 0.1, 0.3 and 1 mM arachidonic acid; 1, 4 and 16 µg/ml collagen; and 20 µM ADP. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 14 days after commencing study medication. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Same IMP but a different (standard) dosing regimen |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will end when the last patient has had the last safety follow-up visit at 14 days after discontinuation of study medication. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |