A Trial to Assess the Safety and Efficacy of Prophylactic TicagrelOr With Acetylsalicylic Acid Versus CLopidogrel With Acetylsalicylic Acid in the Development of Cerebrovascular EMbolic Events During TAVI

• Status: Completed
• Trial end date: 2021-02-01
• Target enrollment: 0
• Participant gender: All

Summary

Ticagrelor administered with Acetylsalicylic Acid (ASA) will provide better cerebral protection from microembolization in the cerebral circulation during Transcatheter Aortic Valve Implantation (TAVI) and 30 days afterwards, than Clopidogrel plus ASA. This hypothesis will be investigated by measuring the number of High Intensity Transient Signals (HITS) as assessed with transcranial Doppler (TCD) on middle cerebral arteries.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Athens
• Treatments: Aspirin; Clopidogrel; Ticagrelor; Ticlopidine

Criteria

Inclusion Criteria:

1. The subject (or where unable to do so, their legally acceptable representative) must be able to provide written informed consent prior to any study specific criteria, stating that he or she understands the purpose of and the procedures required for the study and is willing to participate in the study.

2. Female and/or male subjects aged 18 years or older.

3. High risk (EuroSCOREa ≥18, or considered inoperable) for surgical aortic valve replacement.

4. Is expected to benefit from the placement of TAVI.

5. Does not suffer from any disease or condition that would limit his/her life expectancy of <6 months.

6. The subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.

7. Subjects must meet the following laboratory results from Visit 0 for study inclusion:

1. Hemoglobin ≥ 10 g/dL

2. Platelets ≥ 100 X 103 cells/μL

3. Absolute neutrophil count (ANC) ≥ 1000 cells/μL

4. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels must be within 1.5 times the upper limit of normal (ULN) range for the laboratory conducting the test.

5. Total bilirubin ≤ 2x ULN.

Exclusion Criteria:

1. Have scheduled any elective surgery in the next 4 months following screening procedures.

2. History of hypocoagulopathy.

3. Previous thromboembolism or known hypercoagulopathy (acquired or congenital).

4. Antiplatelet therapy, other than ASA, within 7 days before randomization that cannot be discontinued due to the underlying disease.

5. History of gastric or duodenal ulcer disease verified by endoscopy or barium meal double-contrast technique within the 3 months.

6. Moderate or severe hepatic impairment.

7. Known hypersensitivity to any of the investigational products or their components.

8. Presence of any other clinically significant disease or disorder which, in the opinion of the Investigator (by its nature or by being inadequately controlled), might put the subject at risk due to participation in the study, or may influence the conduct or the interpretation of the results of the study or the subject's ability to complete the study.

9. Any identified contraindication for using Ticagrelor, Clopidogrel or ASA.

10. History or recent findings of atrial fibrillation.

11. Significant carotid artery disease on either internal carotid artery, as defined by a >50 % diameter reduction on carotid ultrasonography.

12. Unwillingness to receive or intolerant to any blood products.

13. Previous trauma or surgery to either femoral vein.

14. Major surgical procedure or trauma within the 30 days prior to enrolment.

15. Mechanical heart valve (any location).

16. Mitral or aortic bioprosthetic valve.

17. The subject is an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.

18. Reproductive status:

1. Women who are pregnant or planning a pregnancy within 1 month of the end of study;

2. Women who are breastfeeding;

3. Women of childbearing potential who are unwilling or unable to use two highly effective methods of birth control to avoid pregnancy for the entire study period, as evaluated by the Investigator. Women who are not of childbearing potential are those that have a history of hysterectomy, bilateral oophorectomy, or are postmenopausal with no history of menstrual flow for ≥ 12 months prior to the screening Visit.

Highly effective methods of birth control are defined as:

Hormonal: established use of oral, implantable, injectable, or transdermal hormonal methods of conception; Placement of an intrauterine device; Placement of an intrauterine system; Mechanical/barrier method of contraception: condom or occlusive cap (diaphragm or cervical/vault cap) in conjunction with spermicide (foam, gel, film, cream or suppository); When used alone, the diaphragm and condom are not highly effective forms of contraception. Therefore the use of additional spermicides provides more effective birth control. However, spermicides alone may not be effective in preventing pregnancy and must be used with a barrier such as a condom or diaphragm.

Surgical sterilization of male partner (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate; for female patients on the study, the vasectomized male partner should be the sole partner for that patient) in conjunction with spermicide, condom, or diaphragm; Sexual true abstinence: when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

19. International normalized ratio (INR) ≥ 2 on the day before the TAVI procedure.

20. History of hemorrhagic stroke, intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular hemorrhage, intracerebral mass or aneurysm, or arteriovenous malformation.

21. Severe left ventricular dysfunction (left ventricular ejection fraction<15%).

22. Severe aortic regurgitation or mitral regurgitation, according to the 2012 European Society of Cardiology and the European Association for Cardio-Thoracic Surgery guidelines (See Appendix 16)

23. Hemodynamic instability (e.g. requiring inotropic or intra-aortic balloon pump support) within 2 hours of the procedure.

24. Subject is dialysis dependent.

25. Any condition requiring the use of anticoagulants that cannot be stopped for the duration of the study.

26. Acute myocardial infarction, major surgery or any therapeutic cardiac procedure (other than balloon aortic valvuloplasty) within 30 days.

27. Gastrointestinal or genitourinary bleed within 30 days.

28. Absolute contraindications or allergy to iodinated contrast that cannot be pre-medicated.

29. Treatment with other investigational drugs (including investigational vaccines) or devices within the 30 days preceding enrolment or planned use of other investigational drugs or devices before the end of the study.

30. Known alcohol or drug abuser.

31. The subject has received any prohibited therapies, as defined in Section 5.7 before the planned first dose of investigational product or is scheduled to receive during the study period. These include, but are not limited to: strong cytochrome P450 3A (CYP3A) inhibitors (ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, erythromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, over 1 litre daily of grapefruit juice), CYP3A substrates with a narrow therapeutic index (cyclosporine, quinidine, simvastatin at doses >40 mg daily, lovastatin at doses >40 mg daily), and strong CYP3A inducers (rifampin/rifampicin, phenytoin, carbamazepine, phenobarbital).