Plain English Summary
Background and study aims
More than one third of the adults with a stroke due to bleeding into the brain - known as brain haemorrhage - are taking drugs to prevent clotting when they have a brain haemorrhage. These patients had previously suffered illnesses like angina, heart attack, or stroke due to blood vessel blockage, which is why they are treated with drugs to prevent further clots occurring. These drugs are usually stopped when the brain haemorrhage occurs. But when patients recover from brain haemorrhage, they and their doctors are often uncertain about whether to restart these drugs to prevent further clots occurring, or whether to avoid them in case they increase the risk of brain haemorrhage happening again. We will study the potentially beneficial effects of three antiplatelet drugs (aspirin, clopidogrel, or dipyridamole) on the risks of heart attack, stroke and other clotting problems as well as their effect on the risk of a brain haemorrhage happening again. This information will help us to decide whether antiplatelet drugs are a promising treatment. If they are, we will recruit a much larger number of patients so that we can determine really reliably whether the beneficial effects of antiplatelet drugs on the risk of clotting outweigh any risks of a repeat brain haemorrhage for such people.
Who can participate?
We aim to recruit 720 men and women in the UK aged 18 years or more who survive a brain haemorrhage. If participants are unable to provide fully informed consent a relative or other legal representative may be approached for their consent.
What does the study involve?
Research staff will collect baseline information about each participant. Some participants may also have an additional MRI scan. Participants will be randomly allocated to either start or avoid antiplatelet medication. Over a period of at least two years we will collect information about participants progress, any medical problems and their adherence to the randomised treatment allocation (start or avoid antiplatelet medication). This follow up information will be obtained from participants, relatives and General Practitioners.
What are the possible benefits and risks of participating?
We do not know whether taking or avoiding antiplatelet medication is best, but participants have a chance to be exposed to the benefit of one or other strategy by participating. Some people find it beneficial to be part of a research study and to be under regular follow-up. The results of this study will help us to treat patients better in future. Participants may find the time spent completing one questionnaire each year inconvenient. Participants, who have agreed to have an MRI scan, may become claustrophobic in the MRI scanner - if this happens the scan would be stopped. Because MRI scans are so detailed, there is also a 1 in 37 chance of finding an abnormality on your MRI scan that is completely incidental to your brain haemorrhage.
Where is the study run from and how long will it last?
RESTART is run by a team at the Division of Clinical Neurosciences at the University of Edinburgh, UK and it will last for at least five years.
When is the study starting and how long is it expected to run for?
Recruitment started on the 2nd May 2013 and will continue until 31st May 2018. Follow-up of these participants will be at least 6 months.
Who is funding the study?
RESTART is funded by the British Heart Foundation
Who is the main contact?
The UK Chief Investigator is Rustam Al-Shahi Salman and the Trial Manager is Karen Innes, and they can be contacted via RESTART.trial@ed.ac.uk.
Trial website
Contact information
Type
Scientific
Primary contact
Mrs Karen Innes
ORCID ID
Contact details
Centre for Clinical Brain Sciences (CCBS)
University of Edinburgh
Chancellor's Building
Room FU303C
49 Little France Crescent
Edinburgh
EH16 4SB
United Kingdom
+44 131 465 9610
karen.innes@ed.ac.uk
Additional identifiers
EudraCT number
2012-003190-26
ClinicalTrials.gov number
Protocol/serial number
14297
Study information
Scientific title
REstart or STop Antithrombotics Randomised Trial
Acronym
RESTART
Study hypothesis
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 drugs result in a beneficial net reduction of all serious vascular events over at least two years compared with a policy of avoiding antiplatelet drugs?
More details can be found at: www.restarttrial.org
Ethics approval
Scotland A Research Ethics Committee, 02/11/2012, ref: 12/SS/0138
Study design
Interventional multicentre parallel group prospective randomised open blinded end-point (PROBE) clinical trial, Design type: Treatment
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Intracerebral haemorrhage
Intervention
1. Patients will be randomised to either 'start antiplatelet medication' (restricted to the use of one or more of aspirin, dipyridamole or clopidogrel at the investigator's discretion) or 'avoid antiplatelet medication'.
2. Additional pre-randomisation brain MRI (for patients participating in the MRI sub-study)
Intervention type
Drug
Phase
Not Applicable
Drug names
Aspirin, dipyridamole, clopidogrel
Primary outcome measure
Current primary outcome measures as of 26/06/2017:
1. Recurrent symptomatic ICH
2. Fatal or non-fatal radiographically- or pathologically-proven recurrent symptomatic
Measured at least 6 months after baseline, detected using annual general practitioner and participant follow-up, with independent, blinded adjudication of the clinical information and investigations relating to every reported outcome
Previous primary outcome measures:
1. Recurrent symptomatic ICH
2. Fatal or non-fatal radiographically- or pathologically-proven recurrent symptomatic
Measured over 2 years after baseline, detected using annual general practitioner and participant follow-up, with independent, blinded adjudication of the clinical information and investigations relating to every reported outcome
Secondary outcome measures
1. Possible recurrent ICH
2. Symptomatic non-fatal extracerebral haemorrhage, extracranial haemorrhage, and vaso-occlusive events
3. Death
4. Modified Rankin Scale score
5. Adherence to antiplatelet drug(s)
1. Fatal events (i.e. followed by death within 30 days): complication of qualifying ICH; symptomatic extradural/subdural/subarachnoid/intraventricular haemorrhage; symptomatic major extracranial haemorrhage; symptomatic vaso-occlusive events; cardiac death with symptoms suggestive of myocardial ischaemia (type 3) or evidence of arrhythmia; deaths from any other known cause; rapidly fatal stroke, consistent with the clinical manifestations of ICH, but without radiographic or pathological confirmation; unwitnessed deaths without a clear cause and without further investigation.
2. Non-fatal events (i.e. not followed by death within 30 days): symptomatic extradural/subdural/subarachnoid/intraventricular haemorrhage; symptomatic major extracranial haemorrhage; symptomatic vaso-occlusive events; non-fatal stroke, with brain imaging performed too late to distinguish ICH from cerebral infarction.
Timepoint: over 2 years after baseline, detected using annual general practitioner and participant follow-up, with independent, blinded adjudication of the clinical information and investigations relating to every reported outcome
Annual ratings of participant function:
Simplified modified Rankin Scale postal questionnaire or Structured telephone interview with non-responders to the postal questionnaire, completed by the participant or their carer.
Overall trial start date
01/04/2013
Overall trial end date
28/02/2021
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Patient age 18 years or over, either sex
2. Spontaneous intracerebral haemorrhage (ICH) not attributable to preceding traumatic brain injury, on the basis of:
2.1. A history from the patient/witness of spontaneous symptom onset without preceding head trauma (head trauma occurring subsequent to ICH symptom onset is permissible)
2.2. brain imaging appearances consistent with spontaneous ICH (which may be accompanied by the brain/bone/soft tissue appearances of trauma occurring subsequently)
2.3. 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)
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 at least 24 hours after ICH symptom onset (randomisation is expected to usually occur when they are 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.
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 720; UK Sample Size: 720
Total final enrolment
537
Participant 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 taking an anticoagulant drug following ICH
4. Patient is pregnant, breastfeeding, or of childbearing age and not taking contraception
5. Patient is being treated or followed up in another Clinical Trial of an Investigational Medicinal Product (CTIMP)
6. Patient and carer unable to understand spoken or written English (local translator is not available)
7. Patients are ineligible for the brain MRI sub-study if they are claustrophobic or they have a contraindication to MRI
Recruitment start date
02/05/2013
Recruitment end date
31/05/2018
Locations
Countries of recruitment
United Kingdom
Trial participating centre
122 Sites in the United Kingdom
EH4 2XU
United Kingdom
Sponsor information
Organisation
University of Edinburgh (UK) and NHS Lothian
Sponsor details
ACCORD
QMRI
47 Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
Sponsor type
University/education
Website
Funders
Funder type
Charity
Funder name
British Heart Foundation (BHF) (UK)
Alternative name(s)
BHF
Funding Body Type
private sector organisation
Funding Body Subtype
Trusts, charities, foundations (both public and private)
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2018 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/29506580
2019 statistical analysis plan in: https://www.ncbi.nlm.nih.gov/pubmed/30909946 [added 27/03/2019]
2019 results in: https://www.ncbi.nlm.nih.gov/pubmed/31128924 (added 29/05/2019)