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 |
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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) |
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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 anti-clotting 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. |
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E.2.2 | Secondary objectives of the trial |
The secondary Study objectives are: 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 |
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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 PRESTIGE-AF 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.
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E.3 | Principal inclusion criteria |
1. Age ≥ 18 years 2. Written informed consent 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)
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E.4 | Principal exclusion criteria |
1. Patient lacks capacity to consent 2. Fully dependent (defined as a modified Rankin Scale score of over 4) 3. Women who are pregnant, breastfeeding, or plan to become pregnant during the Study period 4. Women of childbearing potential (WOCBP) who are unable or unwilling to take measures for effective contraception 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. Another indication for long-term anticoagulation 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 SmPC. Including any of the following: o Hypersensitivity to the active principle or any of the excipients
o Clinically relevant bleeding in progress
o Liver disease associated with coagulopathy and a clinically relevant bleeding risk
o Injuries or conditions such as a significant risk of major bleeding
o Hepatic impairment or liver disease which can have an impact on survival
o Exclusion of patients with end-stage renal creatinine clearance CrCL, (CrCL <15 ml / min) or in patients undergoing dialysis
o Concomitant treatment with other anticoagulants o Patients with a history of thrombosis and antiphospholipid antibody syndrome Special warnings and precautions for use for apixaban, dabigatran, edoxaban, rivaroxaban as per SmPC should also be taken into account at randomisation.
11. Absolute need for antiplatelet agent (APA) at enrolment, meaning that a patient randomised to receive DOAC who would require an APA is not eligible (single APA is permitted in control group only, at time of randomisation). 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 or 5 half-lives of the study drug(observational studies are permitted)
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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. |
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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 |
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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 [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
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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 |
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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 |
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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 | 15 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 30 |