Title: Desmopressin for treatment of patients taking Antiplatelet agents with Stroke due to Haemorrhage
Funder: Department of Health and Social Care

Abstract: Background: Intracerebral haemorrhage is a significant cause of mortality with 3.34 million deaths worldwide in 2015. There is a heavy burden of morbidity with loss of mobility, loss of speech and a high rate of dependency for survivors. Approximately one quarter of intracerebral haemorrhages are in patients taking antiplatelet drugs. These drugs cause a 27% increase in risk of death within one month compared to other patients with intracerebral haemorrhage. At present there are no agents to reverse the effects of antiplatelet drugs. Desmopressin is a drug which acts by stimulating release of Von Willebrand factor (VWF) from endothelial cells, which causes platelets to adhere to areas of endothelial damage. Consequently desmopressin is an appealing treatment to mitigate the effects of antiplatelet drugs. Before embarking on a definitive trial, a feasibility study is proposed to address identification, recruitment, randomisation and follow-up of participants presenting along different hospital pathways. Overall research design: A multicentre, double-blind, randomised feasibility trial of desmopressin for patients with intracerebral haemorrhage who are taking antiplatelet drugs. Setting: Ten acute stroke centres across the UK. Aim: To assess the feasibility of randomising, administering the intervention, and completing follow-up for patients treated with desmopressin or placebo to inform a definitive trial. Target population: Adults (>17 years) with confirmed intracerebral haemorrhage on imaging; less than 12 hours from onset of symptoms [or from when last seen healthy]; prescribed and thought to be taking a daily oral antiplatelet drug in the preceding seven days (cyclooxygenase inhibitors, phosphodiesterase inhibitors or P2Y12 inhibitors); and with signed consent (or waiver of consent). Exclusions: Aneurysmal subarachnoid haemorrhage; haemorrhage known to be due to transformation of infarction, a thrombolytic drug or venous thrombosis; risk of fluid retention; systolic blood pressure Intervention: Desmopressin acetate 0.4 mcg/kg in 50ml 0.9% sodium chloride administered over 20 minutes. All participants will receive standard care in addition to desmopressin or placebo. Comparator: 50ml 0.9% sodium chloride administered over 20 minutes. Feasibility outcome: Number of eligible patients; proportion of eligible patients randomised and reasons for non-randomisation; compliance with intervention; proportion of participants followed up to 90 days and reasons for loss to follow up; proportion of randomised participants with the following data (which is to be collected in the definitive study) available, and reasons for non-availability Primary outcome for the definitive study: Death or dependency at day 90 (modified Rankin scale, shift analysis) Secondary outcomes for the definitive study: Hyponatraemia at 24 hours, early mortality Project timetable: Set up time: 3 months Recruitment: 12 months Follow-up: 3 months Final data cleaning and checks: 1 month Data analysis and dissemination: 3 months Potential benefits to patients and the NHS: If a definitive trial confirms that desmopressin reduces death and disability from intracerebral haemorrhage, these results can be rapidly implemented into routine practice as the drug is inexpensive and already utilised in other fields (congenital bleeding disorders) within the NHS.

Lay abstract: Stroke may be caused by a blood clot forming in the brain &ldquo;ischaemic stroke&rdquo;, or by bleeding into the brain: &ldquo;haemorrhagic stroke&rdquo;. Clot busting drugs are often used to treat ischaemic stroke; but there is no effective drug treatment for haemorrhagic stroke. Stopping or reducing bleeding would be important, because haemorrhagic stroke often leads to death or long-term disability. A quarter of patients with haemorrhagic stroke are taking antiplatelet drugs (such as aspirin) to prevent them having heart attacks or ischaemic strokes. Patients taking these drugs are more likely to die or be disabled if they have a haemorrhagic stroke as the bleeding can be more severe. Desmopressin is a drug that may reverse the effects of antiplatelet drugs and stop bleeding. We would like to run a large randomised trial to see if desmopressin can reduce the number of people who die or are disabled after haemorrhagic stroke. This application is to run a small study to determine whether a large trial is possible and to help in its design. We aim to randomise 50 patients with haemorrhagic stroke who are taking antiplatelet drugs. Sometimes after stroke, patients are unable to give consent, so in this situation we will ask permission for a waiver of consent where the patient is enrolled into the study unless there is a reason that they should not be. Participants will be allocated randomly to one of 2 treatment groups: 1. desmopressin injection 2. placebo injection (an injection that looks like desmopressin but is not a medicine and has no effect of its own). Neither the participant nor the doctor will know if the participant received desmopressin or placebo, this avoids bias in the study. Participants will be interviewed by telephone 90 days after the stroke to assess how well they have recovered.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: STROKE