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 |
Ischämischer Schlaganfallvorbeugung in Patientinnen mit Vorhofflimmern und vorhergehender intrazerebraler Butung |
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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) |
Vorbeugung von Schlaganfall (durch ein verstopftes Blutgefäß) in Patientinnen mit Vorhofflimmern die eine vorhergehende Gehirnblutung hatten |
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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 | 10003658 |
E.1.2 | Term | Atrial fibrillation |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067816 |
E.1.2 | Term | Cardioembolic stroke |
E.1.2 | System Organ Class | 100000004852 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055815 |
E.1.2 | Term | Haemorrhage intracerebral |
E.1.2 | System Organ Class | 100000004852 |
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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 |
Do particular anticlotting drugs called direct oral anticoagulants reduce the rate of ischaemic stroke, that is strokes caused by a blood clot blocking a blood vessel, compared to no anticoagulation (control group) without unacceptably increasing the risk of recurrent brain bleeds in patients with atrial fibrillation and a previous brain bleed within 6 months before enrolment. |
Ist es möglich durch die Einnahme von antithrombotischen Medikamenten, sog. direkten oralen Antikoagulantien (DOAKs), die Rate ischämischer Schlaganfälle (durch eine Verstopfung eines Blutgefäßes) zu reduzieren, im Vergleich zu einer Kontrollgruppe ohne DOAKs, ohne das Risiko einer wiederkehrenden Gehirnblutung in PatientInnen mit Vorhhofflimmern und vorhergehender Gehirnblutung (6 Monate zuvor) zu erhöhen. |
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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. Cardiovasular outcomes include stroke, embolism attributed to blood clot formation, death of any cause or attributed to cardiovascular causes and major adverse cardiac events such as death, cardiac stent thrombosis, recurrent heart attacks. 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 effect of DOACs versus no anticoagulation on net clinical benefit in ICH patients with AF. Net clinical benefit is defined as composite of all stroke, embolic events attributed to blood clots, heart attack, death attributed to cardiovascular causes, and massive bleeding. 4. To explore the impact of DOAC vs. no anticoagulation on quality of life, cognition and psychological morbidity in patients with ICH and AF over time. |
• Untersuchung des Effekts einer Antikoagulation mit DOAK im Vergleich zu keiner Antikoagulation auf schwerwiegende kardiovaskuläre Endpunkte und Sterblichkeit bei PatientInnen mit ICB und VHF. • Vergleich des Effekts von DOAKs im Vergleich zu keiner Antikoagulation in Bezug auf schwerwiegende systemische und intrakranielle Blutungen (Sicherheit). • Untersuchung des klinischen Netto-Benefits von DOAKs im Vergleich zu keiner Antikoagulation bei diesen Patientinnen. • Untersuchung des Einflusses einer antithrombotischen Therapie auf Lebensqualität, Entwicklung kognitiver Defizite und psychologischer Morbidität bei PatientInnen mit ICB und VHF über die Behandlungszeit hinweg. |
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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 |
There are 3 substudies that are described in detail in the appendix of the main study protocol (section 14). The first substudy called "Predictive Modelling of Risk" (Version 1.0 Section 14.1 of PRESTIGE-AF Study Protocol) aims to develop tools for prediction of individual risk of subsequent ischaemic or haemorrhagic strokes in ICH patients with concomitant AF. For this purpose, observational information on clinical characteristics, biological material for genetic analysis and determination of proteins in the blood and brain images will be analysed in parallel to data collection in the main PRESTIGE-AF Study. The second substudy called "longitudinal magnetic resonance Imaging (MRI) Substudy" will enroll 200 PRESTIGEAF participants. Participants of the substudy must have had a brain MRI after their intracerebral haemorrhage (ICH) before study enrolment. Participants of the MRI Substudy will undergo a second brain MRI at their 12-month visit. The aim of this observational prospective Substudy is to clarify the amount of subclinical progression of haemorrhagic and ischaemic damage in ICH patients and test if such dynamics are possibly further predictors of ICH or ischaemic infarction. The third substudy called "Pharmacology Substudy" is exploring adherence to direct anticoagulants and exposure levels in the patient group. Using an innovative technique called the dried blood spot (DBS) sampling technique, single or multiple venous or capillary whole blood samples can be easily collected by Participants or caregivers at various time points within the dosing interval, thus providing objective evidence for DOAC adherence and exposure. Dried blood samples on a paper card will be shipped to a specialised central laboratory which can measure the blood concentrations of DOACs and correlate the findings with Patient characteristics at the end of the study. |
Die TeilnehmerInnen der Hauptstudie werden, wenn Sie dafür in Frage kommen, eingeladen an drei Substudien teilzunehmen, welche folgende Ziele verfolgen: Eine der Substudien wird insbesondere Darstellung der Nutzen/Risiko-Situation der Behandlung (Risikomodellierung) zum Ziel haben. Eine zweite Substudie wird die morphologischen Befunde des Gehirns von Magnetresonanztomographie-Untersuchungen zu Beginn und im Verlauf nützen, um mögliche Vorhersagen bezüglich bestmöglicher Form der Therapie zu treffen. In einer dritten Substudie werden blutbasierte Biomarker und genetische Informationen genützt, um die Vorhersage des individuellen Risikoprofils noch exakter vorzunehmen. |
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E.3 | Principal inclusion criteria |
1. Age ≥ 18 years 2. Written informed consent obtained from the patient, or for patients who lack the capacity to consent this can be provided by an appropriate representative 3. Recent history of a non-traumatic spontaneous ICH during the 6 months before enrolment 4. Documented evidence of AF (paroxysmal, persistent or permanent) CHA2DS2-VASc score≥2 for male, and CHA2DS2-VASc score≥ 3 for female patients 5. Availability of brain imaging following the index Intracerebral Haemorrhage (ICH) 6. Non-traumatic spontaneous ICH within the 12 months before enrolment. Patients become eligible for 14 days after the date of their ICH. |
• Alter ≥ 18 Jahre • Fähigkeit die Studieneinwilligung abzugeben, oder Einwilligung einer gesetzlichen Vertretung • Kürzliche nicht-traumatische intracerebrale Blutung innerhalb 15 Tage bis 6 Monate für Studieneinschluss • Vorhandensein eines VHF (paroxysmal, persistierend, permanent) • CHA2DS2-VASc Score ≥2 für Männer und CHA2DS2-VASc Score ≥3 für Frauen • Verfügbarkeit einer Schnittbilduntersuchung des Hirn nach der ICB und vor Studieneinschluss • Nicht-traumatische ICB innerhalb von 12 Monaten vor Studieneinschluss. Patient*innen können innerhalb von 14 Tagen nach intrazerebrralen Blutung eingeschlossen werden.
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E.4 | Principal exclusion criteria |
1. Fully dependent (defined as a modified Rankin Scale score of over 4) 2. Women who are pregnant, breastfeeding, or plan to become pregnant during the Study period 3. Women of childbearing potential (WOCBP) who are unable or unwilling to take measures for effective contraception 4. ICH occurring before 14 days after the date of ICH 5. ICH occurring longer than 12 months before enrolment 6. ICH resulting from trauma or vascular malformation 7. Another indication for long-term anticoagulation 8. Contraindication for long-term anticoagulant therapy with DOACs (other than ICH) 9. Absolute need for antiplatelet therapy at enrolment 10. Presence of a left atrial appendage occlusion device (LAAO) or plan to implant an LAAO 11. 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 12. Participation in any clinical study with an Investigational Medicinal Product within the past 30 days (observational studies are permitted) |
• Schwer pflegebedürftig (modified Rankin Scale >4) • Schwangere oder stillende Frauen, oder Frauen, die eine Schwangerschaft planen • Gebärfähige Frauen, die keine ausreichende Kontrazeption vornehmen wollen • ICB mindestens 14 Tage vor Studieneinschluss • ICB vor mehr als zwölf Monaten • ICB durch ein Trauma oder eine Gefäßmalformation • Indikation für eine langfristige orale Antikoagulation aus anderem Grund als ein VHF • Medikamentös nicht kontrollierbare arterielle Hypertonie • Jede Kontraindikation (außer der intracerebralen Blutung) zur Behandlung mit Apixaban, Dabigatran, Edoxaban, Rivaroxaban gemäß der jeweiligen Fachinformation • Zwingender Grund für eine Therapie mit Thrombozytenaggregationshemmer • Vorhandener oder geplanter Vorhofohrverschluss (left atrial appendage occlusion, LAAO) • Vorhandensein eines medizinischen, psychologischen oder psychiatrischen Umstandes, der nach Meinung des lokalen Prüfarztes die Studienteilnahme ausschließt • Teilnahme an einer anderen Studie nach AMG in den letzten 30 Tagen (Beobachtungsstudien sind zulässig) |
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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): Ischaemic stroke and recurrent intracerebral haemorrhage. The Study will perform hierarchical testing of the two co-primary endpoints in a parallel group design. |
Es gibt zwei co-primäre binäre Endpunkte der Studie, die in einer Time-to-Event-Analyse evaluiert werden: • Hirninfarkt und • wiederholte intracerebrale Blutungen Die Studie wird ein hierarchisches Testen der beiden co-primären Endpunkte in einem Parallelgruppendesign durchführen. |
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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. |
Endpunkte werden während der Studienteilnahme laufend evaluiert und dokumentiert. |
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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
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 |
• Jedweder Schlaganfall und systemische Embolien • Sterblichkeit jedweder Ursache • Kardiovaskuläre Sterblichkeit • Schwerwiegende kardiale Ereignisse • Klinischer Netto-Benefit, definiert als gemeinsamer Endpunkt von jedwedem Schlaganfall, systemische Embolie, Herzinfarkt, kardiovaskuläre Sterblichkeit und schwerwiegende Blutung |
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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. |
Endpunkte werden während der Studienteilnahme laufend evaluiert und dokumentiert. |
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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 | 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 |
Keine Antikoangulantien |
No anticoagulation |
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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
| 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 | 2 |
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 | 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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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 |