Title: The Metoclopramide and selective oral decontamination for Avoiding Pneumonia after Stroke (MAPS-2) Trial: a 2x2 double-blind, randomized controlled trial of metoclopramide and selective oral decontamination for the prevention of pneumonia in patients with dysphagia after an acute stroke
Funder: Department of Health and Social Care

Abstract: Pneumonia is a major cause of mortality after stroke. It is most frequent in patients who are unable to swallow safely. The main causes of stroke-associated pneumonia are aspiration of pathogenic bacteria from the oropharynx and aspiration of vomited or regurgitated gastric contents. The aim of this study is therefore to test two different approaches to prevention of pneumonia after stroke - reduction of pathogenic oral flora by selective oropharyngeal decontamination and prevention of vomiting by antiemetic therapy and to determine if either or both reduce mortality. This is a phase III multi-centre prospective, double-blind, randomised, placebo-controlled 2x2 factorial trial. Adults with acute moderate to severe neurological impairment and unable to swallow safely [1,2] will be recruited from 50 acute stroke units within 6 h of hospital admission. Patients whose stroke onset was over 12 h before admission, who have already vomited, or who have signs of pneumonia will be excluded. Participants are randomised to: 1. Metoclopramide hydrochloride solution 10 mg (M) [3] OR matching placebo (PM) three times a day iv or via feeding tube -AND to- 2. Selective oropharyngeal decontamination paste (SOD)[4] OR matching placebo (PSOD) applied to the mucous membranes of the mouth four times daily giving the combinations M+SOD, M+PSOD, SOD+PM, PM+PSOD. The intervention will be continued until tube feeding is no longer needed or for a maximum of 21 days. A daily log of vital signs, pneumonia symptoms/diagnosis, antibiotic use, swallowing, vomiting and adverse events will be kept for 14 days. A neurological assessment (NIHSS)[5] will be performed at 30 days, and disability (mRS)[6], current method of feeding, vital status (or date of death), current abode, ‘home time’[9] and date of discharge will be assessed by telephone interview at 90 days along with quality of life (eq5d) [7,8]. Vital status will be recorded for the duration of the study. We have already shown significant reductions in the incidence of pneumonia in pilot trials for each of the two interventions. There was also a non-significant trend towards lower mortality. The main outcome is therefore mortality. This will be tested by competing risks survival analysis. Secondary outcomes include pneumonia [10] at 2 weeks, neurological recovery at 30 days, length of hospital stay, functional recovery, feeding status and quality of life at 90 days. As there are significant treatment costs (both drug and nursing time) and potential savings through faster recovery, a cost effectiveness analysis will also be conducted. A sample size of 1160 participants will give 90% power at a 5% two-tailed significance level to detect a 19% mortality reduction (hazard ratio 0.78) from control (32%) with 10% loss to follow-up and accounting for 10% competing risks. The factorial design will test two interventions at once. We have already established feasibility in two pilot studies. Experience from these and from recruitment to the STROKE-INF study [11], which has similar inclusion criteria, suggests that enrolment of 1 patient/centre/month is realistic. Project timelines (months) are: start-up 0-11, recruitment 0-29, end of follow-up 32, report written and submitted 36. The study team includes collaborators with experience of running large multicentre trials, clinical stroke care, nursing, microbiology, statistics, health economics, trial management and a patient representative.

Lay abstract: People who have had a stroke often lose the ability to swallow. If you cannot swallow properly this can cause food and saliva to get into your airways. If this happens, there is an increased risk of developing pneumonia, which is a life threatening and highly weakening condition. Even treatment with antibiotics may not prevent the weakening effects of pneumonia from delaying recovery, or worsening the condition. In such stroke patients, food is provided through a tube directly into the stomach to prevent food entering the airways. Stroke patients are still at risk however, as moving and turning can lead to vomiting. Vomit can easily be inhaled into airways, especially when lying down. Additionally saliva, containing bacteria that can cause pneumonia when inhaled, can build up as the patient cannot swallow. The MAPS-2 study will test two ways of preventing pneumonia in stroke patients who are being fed through a tube. The first method will be to prevent patients vomiting using a drug called metoclopramide. This drug is well known to prevent vomiting and the NHS use it widely in other patients. The second method is to use an antibiotic paste in the patient’s mouth to reduce the bacteria in their saliva. Both methods have been shown, in smaller separate studies, to decrease the number of patients who develop pneumonia and the number of resulting deaths. All patients recruited will receive a 'drug' and a 'mouth paste' but neither the patient nor the clinicians will know whether the patient is getting a 'real' drug or paste or a placebo. Four groups will be used: 1. metoclopramide and placebo paste 2. metoclopramide and antibiotic paste 3. placebo metoclopramide and antibiotic paste 4. placebo metoclopramide and placebo paste We will enroll 1160 stroke patients with swallowing problems and who are receiving tube feeding into MAPS-2. Patients will be asked to agree to take part within 6 hours of being admitted to hospital. Fifty different hospitals from across the UK will be recruiting patients. Enrolled patients will be allocated to one of the above four groups at random. Patients will then be monitored daily for signs and symptoms of pneumonia, as well as any treatment side effects for 14 days. On day 30, patients will be assessed to see how they are recovering from their stroke (neurologically). On day 90, patients and/or their families will receive a phone call from the MAPS-2 team to see how they are doing physically, how they are eating (is the tube still in), where they are living (home, care home, hospital) and what quality of life is like for them. All collected data will be analysed by the team to see if either treatment can prevent pneumonia and reduce the number of deaths in these patients. Health economics will be analysed to see if cost savings result from preventing pneumonia by reducing length of stay, accelerating rehabilitation and preventing use of systemic antibiotics. Antibiotic resistance is a growing problem and reduction in antibiotic use is an important national target for the NHS.

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