E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
anticoagulation following mechanical heart valve surgery |
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E.1.1.1 | Medical condition in easily understood language |
To prevent the development of blood clots in patients having received a mechanical heart valve |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053349 |
E.1.2 | Term | Pharmacokinetic study |
E.1.2 | System Organ Class | 100000004848 |
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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 |
To validate the dosing algorithm for dabigatran etexilate in patients receiving a mechanical heart valve. |
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E.2.2 | Secondary objectives of the trial |
Clinical safety and efficacy outcome variables, mortality and morbidity endpoints, will all be evaluated in an exploratory manner |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
An echocardiography sub study will be conducted. This will form part of the main study and will be detailed as appendices. They do not have separate titles.
Details will follow by protocol amendment. |
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E.3 | Principal inclusion criteria |
Patients aged 18 -75 years, either undergoing implantation of a mechanical valve during the current hospital stay or having undergone implantation more than three months prior to randomisation. |
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E.4 | Principal exclusion criteria |
1. Patients who have undergone prior valve surgery with implantation of a bioprosthetic or mechanical valve before the index valve replacement surgery.
2. Patients undergoing aortic root replacement and/or replacement of the ascending aorta prior or at index valve replacement surgery..
3. Patients undergoing bioprosthetic or mechanical tricuspid or pulmonary valve replacement.
4. Tricuspid valve repair prior or at index valve replacement in a patient with double valve replacement.
5. Clinically relevant paravalvular leak related to index valve replacement surgery.
6. Active infective endocarditis.
7. Complex congenital heart abnormality.
8. Acute coronary syndrome within 1 month prior to randomisation.
9. Uncontrolled hypertension
10 Emergency surgery or major trauma within three months of randomisation
11. Planned surgery or intervention within one month post randomisation.
12. Any history of haemorrhagic stroke
13. History of intraocular, spinal, retroperitoneal or atraumatic intra articular bleeding unless the causative factor has been permanently eliminated or repaired (e.g. by surgery).
14. Gastrointestinal haemorrhage within the past year, unless the cause has been permanently eliminated (e.g. by surgery) or symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days.
15. Haemorrhagic disorder or bleeding diathesis (e.g. von Willebrand disease, haemophilia A or B or other hereditary bleeding disorder, history of spontaneous intra-articular bleeding, history of prolonged bleeding after surgery/intervention).
16. History of thrombocytopenia, including heparin-induced thrombocytopenia or a platelet count <100 x 10e9/L) at screening
17. Renal impairment (estimated CrCl calculated by Cockcroft-Gault equation) <40mL/min at screening.
18.Liver disease as indicated by at least one of the following:
• Prior and persistent ALT or AST or alkaline phosphatase >3 X upper limit of normal (ULN)
• Active hepatitis C (as evidenced by positive hepatitis C virus ribonucleic acid assay by sensitive polymerase chain reaction (PCR) based assay, such as Roche Monitor or Bayer TMA assay)
• Active hepatitis B (HBs antigen + or anti HBc IgM+)
• Active hepatitis A.
19. Patients who will continue to require treatment with dual antiplatelet therapy.
20. Ongoing or planned treatment with long-term oral anticoagulants for alternative indications during the course of the study (e.g. treatment of VTE, secondary prevention of VTE) with the exception of anticoagulation for stroke prevention in patients with pre-existing AF. Patients with prior use of oral anticoagulants for SPAF or for prevention of thromboembolic events due to the presence of a mechanical heart valve will be allowed to participate in this trial.
21. Patients with a known allergy to dabigatran etexilate or warfarin or their excipients used for the capsule of the drug.
22. Pre-menopausal (last menstruation ≤1 year prior to screening) who:
•Are pregnant or breast feeding or
•Are not surgically sterile or
•Are of child bearing potential and not practising an acceptable method of birth control, or do not plan to continue practising an acceptable method of birth control throughout the trial (highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly.
23. Patients weighing less than 40kg.
24. Patients who have participated in another trial with an investigational drug or device within the past 30 days
25. Patients not willing or able to comply with the protocol requirements or considered unreliable by the Investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, has a life expectancy less than the expected duration of the trial due to concomitant disease, or has any condition which in the opinion of the Investigator, would not allow safe participation in the study (e.g. drug addiction, alcohol abuse).
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E.5 End points |
E.5.1 | Primary end point(s) |
The comparison of observed total dabigatran plasma concentrations values at trough compared to values estimated by dose modelling |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
for A subjects: Day 4-7 following start of dabigatran etexilate; four and twelve weeks
for B subjects: day 0 prior to start of study drug (baseline measurement), and at every subsequent visit |
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E.5.2 | Secondary end point(s) |
clinical efficacy and safety outcome variables will be studies in an exploratory manner |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
full trial duration (12 weeks) |
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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 | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
safety and efficacy in exploratory fashion only |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
all subjects previously treated within A population are discontinued as per protocol version 5 |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Netherlands |
Norway |
Poland |
Sweden |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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Last visit of the last subject undergoing the follow up visit for the trial |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 15 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 15 |
E.8.9.2 | In all countries concerned by the trial days | 0 |