| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ischaemic stroke prevention in patients with atrial fibrillation and previous intracerebral haemorrhage |
| Prevención del ictus isquémico en pacientes con fibrilación auricular y hemorragia intracerebral previa |
|
| E.1.1.1 | Medical condition in easily understood language |
Prevention of stroke (caused by a blood clot) in patients with a heart arrhythmia (atrial fibrillation) who have had a
previous brain bleed (intracerebral haemorrhage) |
| Prevención del accidente cerebrovascular (debido a un coágulo de sangre) en pacientes con arritmia cardíaca (fibrilación auricular) que han tenido hemorragia cerebral previa (hemorragia intracerebral) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| 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 main objective is to perform a RCT to resolve the long-standing management dilemma of antithrombotic stroke prevention in intracerebral haemorrhage (ICH) survivors with comorbid atrial fibrillation (AF). Specifically, it will address the question whether direct oral anticoagulants (DOACs, intervention) provide a more effective option for prevention of ischaemic stroke (IS) and an equally safe option in terms of recurrence of ICH for antithrombotic stroke prevention in survivors of recent ICH compared to no anticoagulation (i.e. no antithrombotic therapy (noAT) or antiplatelet therapy (APA) at Principal Investigator´s discretion). |
| El objetivo principal es realizar un ensayo clínico aleatorizado para resolver el dilema en el manejo de la prevención antitrombótica en pacientes que han presentado una hemorragia intracerebral (HIC) afectos de fibrilación auricular (FA) comórbida. Específicamente, se va a dar respuestas a la pregunta de si los anticoagulantes orales directos (ACOD) pueden ser una opción más efectiva en la prevención de ictus isquémico en pacientes supervivientes de una HIC, comparado con no recibir tratamiento anticoagulante (no tratamiento antitrombótico (noAT) o tratamiento antiagregante, según criterio del Investigador Principal). |
|
| E.2.2 | Secondary objectives of the trial |
1. To examine the effect of anticoagulation with DOAC versus no anticoagulation on major cardiovascular outcomes and mortality in ICH patient with AF
2. To compare the effect of DOACs versus no anticoagulation on major systemic and intracranial bleeding in this Study population (safety)
3. To examine the net clinical benefit of DOACs vs no anticoagulation in ICH patients with AF
4. To explore the impact of antithrombotic therapy on quality of life, development of cognitive deficits and psychological morbidity in patients with ICH and AF over time |
1. Examinar el efecto de la anticoagulación con ACOD versus no anticoagulación sobre los resultados cardiovasculares y de mortalidad en pacientes con HIC y FA.
2. Comparar el efecto de los ACOD versus no anticoagulación sobre el sangrado sistémico e intracraneal en la población del estudio (seguridad).
3. Examinar el beneficio clínico neto de los ACOD versus no anticoagulación en pacientes con HIC y FA.
4. Explorar el impacto de la terapia antitrombótica sobre la calidad de vida, desarrollo de déficits cognitivos y morbilidad psicológica en pacientes con HIC y FA a largo plazo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Ability to provide informed consent
3. Recent history of a non-traumatic spontaneous ICH within 15 days to 6 months before enrolment
4. Presence of AF (paroxysmal, persistent, permanent)
5. CHA2DS2-VASc score ≥2 for male and CHA2DS2-VASc score ≥3 for female patients [15].
6. Availability of a brain scan performed after the ICH and before enrolment |
1. Edad ≥ 18 años.
2. Habilidad para dar el consentimiento informado.
3. Historia reciente de HIC espontánea, no traumática, des de 15 días hasta 6 meses antes de la inclusión al estudio.
4. Presencia de FA (paroxística, persistente o permanente).
5. Resultado en la escala CHA2DS2-VASc ≥2 en hombres y CHA2DS2-VASc ≥3 en mujeres.
• Disponibilidad de una tomografía axial computarizada (TAC) de cráneo realizada tras la HIC y antes de la inclusión en el estudio. |
|
| E.4 | Principal exclusion criteria |
1. Patient lacks the capacity to consent
2. Fully dependent (modified Rankin scale >4)
3. Women who are pregnant, breastfeeding or planning on becoming pregnant
4. Women of childbearing potential (WOCBP 12.1) who are unable or unwilling to take measures for effective contraception (4.8)
5. ICH occurring within the last 14 days before enrolment
6. ICH occurring longer than 6 months before enrolment
7. ICH resulting from trauma or vascular malformation
8. Indication for long-term anticoagulation other than AF
9. Patient has hypertension, which in the opinion of the investigator, is uncontrollable with medication
10. Any contraindication (except intracerebral haemorrhage) to treatment with apixaban, dabigatran, edoxaban, rivaroxaban as per Summary of Product Charasteristics (SmPC)
11. Absolute need for antiplatelet therapy at enrolment
12. Presence of a left atrial appendage occlusion device (LAAO) or plan to implant an LAAO
13. Presence of any medical, psychological, or psychiatric condition which in the opinion of the Principal or Co-Investigator would cause participation in the Study to be unwise
14. Participation in any clinical study with an Investigational Medicinal Product within the past 30 days (observational studies are permitted) |
1. Incapacidad para dar el Consentimiento Informado.
2. Dependencia total (escala de Rankin modificada >4).
3. Mujeres embarazadas, en período de lactancia o con intención de quedarse embarazadas.
4. Mujeres con potencial de quedarse embarazadas que no pueden o no quieren adoptar medidas anticonceptivas efectivas.
5. HIC durante los últimos 14 días antes de la inclusión en el estudio.
6. HIC hace más de 6 meses des de la fecha de inclusión en el estudio.
7. HIC secundaria a traumatismo o malformación vascular.
8. Pacientes con indicación para anticoagulación a largo plazo que no sea FA.
9. Pacientes con hipertensión que, según la opinión del investigador, no se pueda controlar con medicación.
10. Cualquier contraindicación (excepto HIC) para el tratamiento con apixaban, dabigatran, edoxaban, rivaroxaban, según la Ficha Técnica.
11. Necesidad absoluta de recibir tratamiento antiagregante en el momento de la inclusión.
12. Presencia de un dispositivo de cierre de la orejuela auricular izquierda (LAAO; Left Atrial Appendage Occlusion device), o intención de implantarlo.
13. Presencia de cualquier enfermedad médica, psicológica o psiquiátrica que, según la opinión del investigador, pueda alterar la participación en el estudio.
14. Haber participado en un ensayo clínico con un producto medicinal en investigación durante los últimos 30 días (los estudios observacionales están permitidos). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| There are two co-primary binary endpoints in the Study (evaluated by time-to-event analysis): IS and recurrent ICH. The Study will perform hierarchical testing of the two co-primary endpoints in a parallel group design |
| Este ensayo clínico tiene dos variables binarias co-primarias (evaluadas mediante análisis de supervivencia): ictus isquémico y HIC recurrente. Se realizará un análisis jerárquico de las dos variables co-primarias mediante un diseño paralelo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Anytime during follow-up period the end points will be evaluated and adjudicated |
| En cualquier momento durante el período de seguimiento, las variables serán evaluados |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints are
1. all stroke and systemic embolism
2. all-cause mortality
3. cardiovascular mortality
4. major adverse cardiac events
5. net clinical benefit defined as composite endpoint of all stroke, systemic embolic event, myocardial infarction, cardiovascular mortality, and major bleeding [14].
Secondary safety endpoints comprise of
1. any major haemorrhage according to International Society of Thrombosis and Hemostasis (ISTH) bleeding assessment tool
2. any intracranial haemorrhage |
Las variables secundarias de eficacia son
1. Todos los ictus y eventos embólicos sistémicos.
2. Mortalidad por todas las causas.
3. Mortalidad cardiovascular.
4. Eventos adversos cardíacos mayores.
5. Beneficio clínico neto definido como una variable compuesta de: ictus, eventos embólicos sistémicos, infarto de miocardio, mortalidad cardiovascular y hemorragia mayor.
Las variables secundarias de seguridad son:
1. Cualquier hemorragia mayor, definida según la escala de hemorragia de la International Society of Thrombosis and Hemostasis (ISTH).
2. Cualquier hemorragia intracraneal. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Anytime during follow-up period the end points will be evaluated and adjudicated |
| En cualquier momento durante el período de seguimiento, las variables serán evaluados |
|
| 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 | No |
| 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 | 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) | Yes |
| 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 | 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 |
| Sin anticoagulación |
| No anticoagulation |
|
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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