| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with left ventricular disfunction with ejection fraction less or equal to 35%. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019279 |
| E.1.2 | Term | Heart failure |
|
| 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 Primary Specific Aim of this randomized, double-blind, multi-center clinical trial is to determine whether warfarin (International Normalized Ratio [INR] 2.5-3.0, target INR 2.75) or aspirin (325 mg per day) is superior for preventing all-cause mortality and stroke combined in patients with ejection fraction (EF) greater or less than 35%, when balanced against any risk of intracerebral hemorrhage. |
|
| E.2.2 | Secondary objectives of the trial |
1 Is warfarin or aspirin superior for reducing stroke alone?
2 Among women, is warfarin or aspirin therapy superior for reducing all-cause mortality, stroke, and MI combined, when balanced against any increased risk of intracerebral hemorrhage?
3 Does any relative risk or benefit of warfarin or aspirin for stroke, TIA, or peripheral embolism depend on ejection fraction?
4 Does any relative risk or benefit of warfarin or aspirin depend on NYHA class or on etiology of cardiac failure ?
5 Do warfarin and aspirin differ in their effect on cognitive function?
6 Does warfarin have a larger risk reduction relative to aspirin in cardioembolic than other stroke subtypes?
7 Are cardioembolic infarcts more frequent in non-ischemic than ischemic cardiac disease?
10 Are cardioembolic infarcts more frequent in women than in men?
11 Is mean cerebral infarct volume depend on EF ? |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Cardiac EF less than or equal to 35% by radionuclide ventriculography, left ventriculography or quantitative echocardiographic measurement or an echocardiographic Wall Motion Index of less than or equal to 1.2, within three months of enrollment. The patient’s clinical cardiac state at enrollment should be similar to their state at the time of the qualifying echocardiogram. The qualifying left ventricular function measurement must be obtained at least 3 months after an MI, coronary artery bypass grafting, PTCA, and at least one month after pacemaker insertion. Patients scheduled for mitral valve repair should have qualifying echo after surgery.
2. Modified Rankin score less than or equal to 4.
3. Patient must be taking ACE inhibitors. If intolerant of ACE inhibitor patient must be on angiotensin II receptor blockers or hydralazine and nitrates.
4. Patient is able to follow an outpatient protocol (requiring monthly blood tests and clinic visits every four months for the duration of the study) and is available by telephone.
5. Patient understands the purpose and requirements of the study, can make him/herself understood, and has provided informed consent.
6. Patients with recent stroke or TIA within twelve (12) months will be eligible to be included in the RS (recent stroke) subgroup.
7. Chronic CHF patients (NYHA I – IV) admitted to the hospital can be randomized prior to discharge if the patient is stable, taking oral medications for 24 hours and ambulatory at the time of discharge. Stable New York Heart Association Class IV patients will be eligible for randomization. |
|
| E.4 | Principal exclusion criteria |
1. The presence of any of the following unequivocal cardiac sources of embolism: chronic or paroxysmal AF, mechanical valve, endocarditis, intracardiac mobile or pedunculated thrombus, and valvular vegetation.
2. Cyanotic congenital heart disease, Eisenmenger’s syndrome.
3. Decompensated heart failure.
4. Cardiac surgery, angioplasty, or MI within the past 3 months.
5. A contraindication to the use of either warfarin or aspirin, e.g. active peptic ulcer disease, active bleeding diathesis, platelets <100,000*, hematocrit <30, INR >1.3 (if not on warfarin), clotting factor abnormality that increases the risk of bleeding, alcohol or substance abuse, severe gait instability, cerebral hemorrhage, systemic hemorrhage within the past year, severe liver impairment (AST >3x normal*, cirrhosis), any condition requiring regular use of non-steroidal anti-inflammatory agents, allergy to aspirin or warfarinuncontrolled severe hypertension (systolic pressure >180 mm Hg or diastolic pressure > 110 mm Hg), positive stool guaiac (occult blood) not attributable to hemorrhoids, creatinine >3.0*(US) 286 mmol/L (UK). (*on most recent test done within 30 days prior to randomization)
6. Patient needs continuing therapy with intravenous heparin, low molecular weight heparin or a specific antiplatelet agent.
7. Dementia or psychiatric or physical problem that prevents the patient from following an outpatient program reliably.
8. Comorbid conditions that may limit survival to less than five years.
9. Pregnancy, or female in age of childbearing potential who is not sterilized or is not using a medically accepted form of contraception* (see procedure manual).
10. Enrollment in another study that would conflict with the current study.
11. Hospitalization for new diagnosis of onset of CHF within past one month or carotid endarterectomy or pacemaker insertion within the past month.
12. Children under the age of 18 years.
*A pregnancy test is required for all women of childbearing age. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the first to occur of the following three events: death from any cause; ischemic stroke (with any degree of subsequent hemorrhagic conversion); or primary intracerebral hemorrhage (symptomatic or asymptomatic).
A.1.1 All-cause Mortality Death from any cause, whether related to the study medications or not, is a primary endpoint. Site Investigators will report a cause of death, but final cause of death is adjudicated by the Cardiac Adjudication Committee. See Section A.3 below for definitions of causes of death.
A.1.2 Ischemic Stroke When a patient develops a new focal neurological deficit that is sudden in onset and is thought to have a vascular cause, the patient must be screened for ischemic stroke by CT or MRI, as well as by clinical symptoms. Ischemic stroke is diagnosed when: • The focal deficit lasts at least 24 hours (even if the imaging scans do not identify a new infarct), or: • A CT or T1/T2 MRI shows a new infarct relevant to the clinical symptoms (even if the deficit lasts less than 24 hours). A new abnormality on diffusion-weighted MRI is not itself sufficient to confirm ischemic stroke. The deficit must also be seen on subsequent CT or T1/T2 MRI to be evidence of a recent cerebral infarct. A retinal or ocular infarct does not constitute a primary endpoint.A.1.2.1 Hemorrhagic Conversion of Ischemic Stroke Hemorrhagic conversion of ischemic stroke is hemorrhagic change within an acute ischemic lesion. Imaging may reveal various degrees of hemorrhagic change. Hemorrhagic conversion is identified by CT or MRI as follows: 1. By CT: patchy areas of high attenuation with indistinct margins that have a speckled or mottled appearance (petechial hemorrhage) within an area of low attenuation (the infarct) 2. By MRI: i) Acute: patchy hypointense foci on T2-weighted imaging that are surrounded by edema; ii) Subacute: patchy hyperintense foci on both T1- and T2-weighted imaging that are surrounded by edema. A symptomatic hemorrhagic conversion is one whose onset is associated with any clinical deterioration.
A.1.3 Primary Intracerebral Hemorrhage 1. CT definition: a homogeneous region of high attenuation that is usually associated with mass effect. 2. MRI definition: i) Hyperacute: a well circumscribed area that is isointense with gray matter on T1-weighted imaging and hyperintense on T2-weighted imaging, ii) Acute: a well circumscribed area that is isointense with brain on T1-weighted imaging and profoundly hypointense on T2-weighted imaging, iii) Subacute: a well circumscribed area that is hyperintense on both T1- and T2-weighted imaging. |
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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 | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.3 |
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 | 7 |
| 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 | Information not present in EudraCT |
| 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 |
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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
|
| It is provided in study protocol. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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