Title: Remote Ischaemic Conditioning After Stroke 3 (RECAST-3): A multicentre randomised controlled trial
Funder: Medical Research Council

Abstract: Strokes are very common with ~100 000 strokes occurring every year in the UK. The majority (80%) are caused by a blocked blood vessel and others are caused by a ruptured blood vessel. There are very few treatments for strokes, such as using medicines or wires to unblock blood vessels, but they can only be used in a small proportion of strokes caused by blocked blood vessels._x000D_ _x000D_ A treatment called ‘remote ischaemic conditioning’ (RIC) could help protect the brain from damage caused by stroke. RIC is performed by inflating a blood pressure cuff on the arm, which briefly interrupts its blood supply; the cuff is deflated after 5 minutes and the cycle is repeated 4 times. The process causes body chemicals to be released into the blood stream which have a protective effect on the brain and may reduce the size of the stroke and reduce disability – this has been shown in experimental models of stroke but the treatment has not been proven in humans. _x000D_ _x000D_ We have completed a small trial of 26 stroke patients (called RECAST-1) which used RIC soon after their stroke - RIC was very well tolerated and caused minimal side-effects. We have also completed a second trial (RECAST-2) of 60 stroke patients showing we can perform RIC urgently within 6 hours of new stroke symptoms. The trial has also suggested that RIC may be able to prevent ongoing damage caused by stroke._x000D_ _x000D_ We will perform a trial across 60 UK hospitals including 1300 stroke patients called RECAST-3. Half of the participants will receive RIC, and the other half will have a dummy procedure performed (a placebo). Patients will be identified and invited to take part in the trial by the Stroke Team as soon as they arrive in hospital. The participants will have a 50:50 chance of receiving RIC or the placebo procedure. RIC or placebo is performed twice on the first day and twice on day two. Consent can be given by a relative or carer if the patient is not able to give it themselves. This will occur at the same time as routine treatments (such as receiving clot-busting medicine). The participant will be seen regularly by the research team during admission to answer questions on the trial treatment. After discharge from hospital, the participant will be contacted over the telephone 3 months later to answer questions about their physical ability, mood, memory and quality of life._x000D_ _x000D_ It is likely that new treatments will have their greatest effect if administered in the first few hours after a stroke. RIC is an attractive potential treatment since it would be simple and cheap to administer by medics, other healthcare professionals (nurses, paramedics) or even non-medically trained personnel. If this study shows that RIC is beneficial in reducing stroke recurrence and leads to a lower level of disability, it would have significant social, medical and financial benefit to patients, families and society.

Lay abstract: Hypothesis: Remote ischaemic perconditioning (RIC) improves functional outcome in patients presenting with hyperacute stroke._x000D_ _x000D_ Background: Stroke is common with one stroke occurring in the UK every 5 minutes. It can be devastating to patients and carers, and costs the NHS ~£9 billion/year. Remote ischaemic conditioning (RIC) uses repeated cycles of transient limb ischaemia and, experimentally, can help protect the brain from injury. It can be performed before (preconditioning), during (perconditioning) or after (postconditioning) an ischaemic insult by inflating & deflating a blood pressure cuff on the arm. We have completed a pilot trial (RECAST) showing RIC is well tolerated after acute stroke and augments serum levels of neuroprotective proteins (heat shock proteins, HSP). RECAST-2, a phase IIb study, has demonstrated feasibility of repeated doses of RIC in hyperacute stroke (<6 hours). _x000D_ _x000D_ Aim: To perform a multicentre randomised controlled trial assessing remote ischaemic conditioning (RIC) in patients with hyperacute ischaemic stroke._x000D_ _x000D_ Design: Phase III prospective randomised (1:1) sham-controlled blinded-endpoint parallel-group multicentre trial._x000D_ _x000D_ Population: 1300 adults with hyperacute ischaemic stroke presenting to 60 Emergency Departments and Stroke Units in the UK._x000D_ _x000D_ Intervention: RIC group: 4 cycles of intermittent limb ischaemia - alternating 5 minutes inflation (+20 mmHg above systolic BP) followed by 5 minutes deflation of an automated upper arm blood pressure cuff. _x000D_ Comparator: Sham RIC. An automated upper arm blood pressure cuff is inflated to 20 mmHg for 4 cycles (5minutes inflation/5 minutes deflation)._x000D_ Treatment Duration: 1st dose (4 cycles of RIC or sham) within <6 hours of onset. Second dose 1-2 hours after the first dose. Twice daily until end day 2; total 4 doses._x000D_ _x000D_ Primary outcome: Death or dependency at day 90 (modified Rankin Scale [mRS], ordinal shift analysis) recorded using central blinded telephone follow-up. _x000D_ _x000D_ Secondary outcomes (day 90): Cerebrovascular events; major adverse cardiac and cerebral events; acute kidney injury; disability; cognition; mood; frailty; quality of life; safety (death; neurological deterioration; intracranial haemorrhage, systemic embolism, serious adverse events)._x000D_ _x000D_ Sample size: Assuming alpha=0.05, power=90%, losses to follow up=5% and covariate adjustment reducing sample size by 20%, a sample size of 1300 will be needed to detect a treatment effect of OR 0.75 by shift analysis of mRS._x000D_ _x000D_ Mechanisms: Ischaemic reperfusion injury (Day 2 CT brain: intracranial haemorrhagic, swelling of original stroke, recurrent ischaemic stroke); mechanical thrombectomy substudy (Day 7 MRI; infarct growth and volume, oedema, perfusion)._x000D_ _x000D_ Timeframe: 45 months (M) with 33M recruitment in 60 centres. M0-6: trial set up, centre initiation & training (site initiation will be performed over the telephone); M3-36: recruitment; M37-39: Final day 90 Follow-ups (primary outcome); M40-45: Data clean & lock, analysis & dissemination_x000D_ _x000D_ Impact: Improvements in functional outcome after a stroke will benefit patients in promoting independence and decreasing care needs in terms of physical, psychological and carer burden. RIC is an attractive prospect since it would be cheap & simple to administer by medics, allied health professionals, or non-medically qualified personnel.

Research activity codes: 5.3 MEDICAL DEVICES
Health categories: STROKE