| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Spontaneous Intracerebral Haemorrhage (ICH) |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 10022753 |
| E.1.2 | Term | Intracerebral haemorrhage |
| 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 |
For adults surviving spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, does a policy of starting antiplatelet therapy result in a beneficial net reduction of all serious vascular events over two years compared with a policy of avoiding antiplatelet therapy?
The primary objective of the pilot phase is to estimate, when all participants have completed at least two years of follow-up, the relative and absolute effects of antiplatelet drugs on the risk of brain haemorrhage happening again associated with a policy of starting antiplatelet drugs after the acute phase of brain haemorrhage. Ultimately, we want to determine whether antiplatelet drugs are beneficial for patients after brain haemorrhage because the gains from prevention of clotting problems outweigh the risks of bleeding at any site. This pilot phase of the trial may roll seamlessly i |
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| E.2.2 | Secondary objectives of the trial |
| To determine whether patients with tiny deposits of blood in the brain called 'microbleeds' on brain magnetic resonance imaging (MRI) have an increased risk of having a recurrent brain haemorrhage if prescribed antiplatelet drugs following a brain haemorrhage. |
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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 |
The brain MRI sub-study is incorporated into the current protocol.
Brain microbleeds on MRI appear to be a biomarker of bleeding-prone microangiopathies (such as arteriolosclerosis and cerebral amyloid angiopathy), they predict recurrent ICH, and lobar microbleeds also appeared to modify the effect of aspirin on recurrent ICH risk in one observational study. Furthermore, a collaborative meta-analysis of case-case comparisons has found a preponderance of brain microbleeds amongst patients who had an ICH whilst taking antiplatelet drugs compared to those who were not on any antithrombotics when they had an ICH. So we intend to perform a brain MRI sub-study in ~550 of the 720 participants to better understand these micro-angiopathies by exploring whether there is a statistical interaction between the presence, number, or location of brain microbleeds and the effect of antiplatelet drugs on the primary outcome. |
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| E.3 | Principal inclusion criteria |
1. Patient age ≥18 years.
2. Spontaneous ICH
o not attributable to preceding traumatic brain injury, on the basis of:
a history from the patient/witness of spontaneous symptom onset without preceding head trauma (head trauma occurring subsequent to ICH symptom onset is permissible)
brain imaging appearances consistent with spontaneous ICH (which may be accompanied by the brain/bone/soft tissue appearances of trauma occurring subsequently)
o either ‘secondary’ to an underlying structural cause (e.g. aneurysm, tumour, arteriovenous malformation, or intracranial venous thrombosis), or ‘primary’ (if the investigator either does not suspect an underlying structural cause, or it is not detected by further radiographic investigation).1,44
3. Patient had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease for any length of time before the onset of the qualifying ICH.
4. Patient is approaching the end of their hospital admission/assessment for the qualifying ICH.
5. Patient and their doctor are both uncertain about whether to start or avoid antiplatelet drugs.
6. Patient is registered with a general practitioner (GP).
7. Brain imaging study that first diagnosed the qualifying ICH is available.
8. Consent to randomisation from the patient (or personal / legal / professional representative if the patient does not have mental capacity).
9. If eligible for the brain MRI sub-study, the MRI must be performed after the ICH but before randomisation. |
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| E.4 | Principal exclusion criteria |
1. ICH due to traumatic brain injury, in the opinion of the investigator.
2. ICH due to haemorrhagic transformation of an ischaemic stroke, in the opinion of the investigator.
3. Patient is pregnant, breastfeeding, or of childbearing age and not taking contraception.
4. Patient is being treated or followed up in another CTIMP.
5. Patient and carer unable to understand spoken or written English (and local translator is not available).
6. Patients are ineligible for the brain MRI sub-study if they are claustrophobic or they have a contraindication to MRI. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Fatal or non-fatal radiographically- or pathologically-proven recurrent symptomatic intracerebral haemorrhage (ICH).
We define ICH as the abrupt onset of headache, altered level of consciousness, or focal neurological deficit, anatomically referable to a focal collection of blood predominantly located within the brain parenchyma (diagnosed on brain imaging or at autopsy), which was not attributable to prior trauma or haemorrhagic transformation of an ischaemic stroke. This also applies when neurological deterioration occurs with radiographic or pathological evidence of ICH volume growth early after the qualifying ICH (due to either haematoma expansion or re-bleeding). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| This outcome will be evaluated using survival analysis techniques for its occurrence over at least two years. |
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| E.5.2 | Secondary end point(s) |
A. Fatal events (i.e. followed by death within 30 days):
1. Complication of qualifying ICH
(a) Neurological deterioration (e.g. hydrocephalus or perihaematomal oedema)
(b) Non-neurological complications (e.g. pneumonia)
2. Symptomatic extradural haemorrhage, subdural haemorrhage, subarachnoid haemorrhage, or intraventricular haemorrhage (not accompanying spontaneous ICH)
3. Symptomatic major extracranial haemorrhage, sub-divided by site (requiring transfusion or endoscopic treatment or surgery, or resulting in death within 30 days)
4. Symptomatic vaso-occlusive events: transient ischaemic attack, ischaemic stroke, unstable angina (www.outcomes-umassmed.org/grace/Files/Standard_Definitions.pdf), acute spontaneous myocardial infarction (type 1),40 peripheral arterial occlusion, mesenteric ischaemia, retinal arterial occlusion, deep vein thrombosis or pulmonary embolism.
5. Cardiac death with symptoms suggestive of myocardial ischaemia (type 3),40 or evidence of arrhythmia
6. Deaths from any other known cause
7. Rapidly fatal stroke, consistent with the clinical manifestations of ICH, but without radiographic or pathological confirmation
8. Unwitnessed deaths without a clear cause and without further investigation
B. Non-fatal events (i.e. not followed by death within 30 days):
1. Symptomatic extradural haemorrhage, subdural haemorrhage, subarachnoid haemorrhage, or intraventricular haemorrhage (not accompanying spontaneous ICH)
2. Symptomatic major extracranial haemorrhage, sub-divided by site (requiring transfusion or endoscopic treatment or surgery)
3. Symptomatic vaso-occlusive events: transient ischaemic attack, ischaemic stroke, unstable angina, myocardial infarction, peripheral arterial occlusion, mesenteric ischaemia, retinal arterial occlusion, deep vein thrombosis or pulmonary embolism.
4. Non-fatal stroke, with brain imaging performed too late to distinguish ICH from cerebral infarction
5. Annual ratings of participant function completed by participant or their carer:
(a) Simplified modified Rankin Scale postal questionnaire
(b) Structured telephone interview with non-responders to the postal questionnaire |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
These outcomes will be evaluated using survival analysis techniques for their occurrence over at least two years.
Further analyses, such as the effect on the composite endpoint of all serious vascular events (which would be likely to be the primary outcome in the main phase of the trial), will be specified in our statistical analysis plan. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | 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 |
| A policy of avoid antiplatelet agents (ATC B01AC Platelet aggregation inhibitors excluding heparin) |
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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 | 99 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | Information not present in EudraCT |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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