Title: The Metoclopramide for Avoiding Pneumonia after Stroke (MAPS-2) Trial: a single-blind, randomized controlled trial of metoclopramide for the prevention of pneumonia in patients with dysphagia after an acute stroke
Funder: Department of Health and Social Care

Abstract: What is the problem?_x000D_ Stroke is the fourth most common cause of death in the UK. Despite great progress over the last 20 years, the only treatments shown to reduce mortality are admission to a specialist stroke unit, prevention of blood clots by leg pumps, and surgery for brain swelling. Pneumonia is the most common cause of death after stroke and, even if not fatal, weakens the patient and delays recovery. Patients with a stroke often lose the ability to swallow safely. This can lead to food and drink spilling into the lungs. Stroke patients with swallowing problems are therefore at high risk of pneumonia. _x000D_ _x000D_ When stroke patients are turned in bed, moved, or even when just resting in bed, they often vomit and inhale the contents of the mouth and/or stomach into the lungs. This is the most common cause of pneumonia after stroke. In a small pilot study conducted in a single hospital we were able to show that metoclopramide, an anti-sickness drug, prevents pneumonia in patients with severe stroke when given regularly in the first two weeks. The aim of MAPS-2 is to confirm this finding in a wider range of hospitals and to establish whether this can also reduce the number of patients who die from stroke. _x000D_ _x000D_ What will we find out?_x000D_ The MAPS-2 study will test whether metoclopramide (10 mg 3 times a day), given early after stroke onset and continued for two weeks, is better than sham control (dummy treatment) for preventing pneumonia and death after stroke. _x000D_ _x000D_ How will we do this?_x000D_ We will enrol 2100 patients with a severe stroke and swallowing problems within 9 hours of stroke onset from 90 or more hospitals in the UK. Once a patient (or a legal representative on their behalf) agrees to take part in the study, they will be allocated randomly to one of the two treatment groups. For each patient, a daily log of whether they have signs or symptoms of pneumonia and if they have any side effects will be recorded for two weeks. A neurological assessment, to see how the patient is recovering from their stroke, will be made on day 14. After six months, the patient or their carer will be telephoned by a member of the study team to assess: their level of disability (if any); their quality of life; whether they still have problems swallowing; if they are still in hospital or, if not, where they are living. A health economic analysis will be done to look at potential cost savings. _x000D_ _x000D_ Who are we?_x000D_ Our research team includes collaborators with experience of running large multicentre trials, clinical stroke care, pneumonia, statistics, health economics, trial management, and two patient representatives. Members of our patient and carer research group have contributed to the development of this study from the start. They have advised on details of patient recruitment in the emergency situation, the evaluation of risks and benefits, the importance of mortality as a main outcome, and procedures for follow-up, and they will be represented in trial management and steering groups. _x000D_ _x000D_ How will we share our results?_x000D_ The results of this study will be presented at national and international conferences, published in peer-reviewed scientific journals, and shared via stroke patient groups such as the Stroke Assembly. The findings will inform National Stroke Guidelines and the National Institute for Health and Care Excellence (NICE) to embed in routine clinical care.

Lay abstract: BACKGROUND: Stroke is the most common cause of death worldwide and the foremost cause of complex disability in the UK. Pneumonia causes more deaths after stroke than the neurological damage. Stroke-associated pneumonia is caused by aspiration of vomited and regurgitated gastric content. Metoclopramide, an antiemetic with both central and peripheral actions, was associated with less pneumonia and a trend to fewer deaths in our pilot study._x000D_ _x000D_ RESEARCH QUESTION: Does metoclopramide, given early after stroke onset and continued for 14 days, reduce mortality and prevent pneumonia?_x000D_ _x000D_ DESIGN: Two-arm parallel group, single blind randomized controlled trial with an internal pilot _x000D_ _x000D_ SETTINGS: Emergency departments and stroke units of 90 or more NHS hospitals_x000D_ _x000D_ POPULATION:_x000D_ Inclusion criteria_x000D_ 1. Adult patients admitted to hospital with a diagnosis of acute stroke and_x000D_ 2. Within 9 hours of symptom onset and _x000D_ 3. Moderate to severe neurological impairment (NIHSS 10 or greater) and _x000D_ 4. Dysphagia (assessed by bedside clinical screen)_x000D_ _x000D_ Exclusion criteria _x000D_ 1. Probable or definite pneumonia at screening_x000D_ 2. Contraindications to metoclopramide _x000D_ 3. Pregnant or breast feeding _x000D_ 4. Co-morbid conditions with life expectancy <3 months _x000D_ 5. Inability to gain consent (patient or legal representative) or consent declined _x000D_ _x000D_ HEATH TECHNOLOGIES BEING ASSESSED_x000D_ Intervention: Metoclopramide solution for injection 10 mg/2 ml three times a day by slow iv injection or via nasogastric tube. For participants < 60 kg the dose will be reduced to 5 mg three times a day for 14 days_x000D_ Comparator: Normal saline solution for injection (sham control) 2 ml three times a day by slow iv injection or via nasogastric tube for 14 days_x000D_ _x000D_ MEASUREMENT OF OUTCOMES AND COSTS: Participants will be followed at 14 days by the local team and at 6 months by telephone (or email/letter if telephone not possible) by the MAPS-2 team._x000D_ _x000D_ PRIMARY OUTCOME: All-cause mortality (time to event) by 6 months_x000D_ _x000D_ Secondary Outcomes at 14 days _x000D_ 1. Pneumonia (clinician diagnosis) _x000D_ 2. Pneumonia (criteria-based)_x000D_ 3. No of days of antibiotic treatment _x000D_ 4. Recovery of swallow (DSRS)_x000D_ 5. Neurological recovery (NIHSS Stroke Scale)_x000D_ 6. Quality of life (EQ-5D™) _x000D_ Secondary outcomes at 6 months _x000D_ 1. Level of disability (modified Rankin Scale) _x000D_ 2. Recovery of swallow (DSRS)_x000D_ 3. Frailty (CFS)_x000D_ 3. Home time _x000D_ 4. Quality of life (EQ-5D™)_x000D_ Secondary outcome at 12 months: all cause-mortality (time to event)_x000D_ _x000D_ HEALTH ECONOMIC ANALYSIS: A cost-effectiveness analysis will be undertaken to determine the cost per death avoided and a cost-utility analysis to determine the cost per quality-adjusted life year (QALY) gained._x000D_ _x000D_ STUDY SIZE: 2100 participants in total _x000D_ _x000D_ TIMELINES: After 6 months set-up time we will open 90 sites within 12 months and recruit 0.9 participants/site/month. The period for recruitment will be 32 months with an internal pilot during the first 9 months. The total duration of the project will be 48 months._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION: Metoclopramide is cheap, widely available, and easy to use. If the trial confirms that it is effective, there would be no barriers for immediate implementation with the potential to save lives nationally and worldwide. Results will be disseminated through publication in high impact journals, conference presentations, clinical research networks, via patient and public representatives, and feed into guidelines and clinical practice.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;STROKE