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

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.

RESEARCH QUESTION: Does metoclopramide, given early after stroke onset and continued for 14 days, reduce mortality and prevent pneumonia? DESIGN: Two-arm parallel group, single blind randomized controlled trial with an internal pilot SETTINGS: Emergency departments and stroke units of 90 or more NHS hospitals

POPULATION: Inclusion criteria 1. Adult patients admitted to hospital with a diagnosis of acute stroke and 2. Within 9 hours of symptom onset and 3. Moderate to severe neurological impairment (NIHSS 10 or greater) and 4. Dysphagia (assessed by bedside clinical screen) Exclusion criteria 1. Probable or definite pneumonia at screening

2. Contraindications to metoclopramide 3. Pregnant or breast feeding 4. Co-morbid conditions with life expectancy <3 months 5. Inability to gain consent (patient or legal representative) or consent declined HEATH TECHNOLOGIES BEING ASSESSED

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

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

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. PRIMARY OUTCOME: All-cause mortality (time to event) by 6 months Secondary Outcomes at 14 days 1. Pneumonia (clinician diagnosis)

2. Pneumonia (criteria-based) 3. No of days of antibiotic treatment 4. Recovery of swallow (DSRS) 5. Neurological recovery (NIHSS Stroke Scale) 6. Quality of life (EQ-5D™) Secondary outcomes at 6 months 1. Level of disability (modified Rankin Scale) 2. Recovery of swallow (DSRS) 3. Frailty (CFS) 3. Home time

4. Quality of life (EQ-5D™) Secondary outcome at 12 months: all cause-mortality (time to event)

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. STUDY SIZE: 2100 participants in total

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.

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.