Title: Treating Oesophageal Atresia to prevent STricture (TOAST)
Funder: Department of Health and Social Care

Abstract: Oesophageal atresia is a rare (about 1 in 2,500–3,000 births) condition where babies are born without an intact oesophagus (swallowing tube) and usually have a connection between their trachea (windpipe) and their stomach instead. It requires urgent lifesaving surgery in the first days of life. In the UK, every year around 150 babies are born with this condition._x000D_ _x000D_ The surgery rebuilds the oesophagus. This is usually successful but sometimes there are problems. One of these problems is reflux where the acid content of the stomach comes back into the oesophagus and can cause regurgitation of feeds and/or damage to the oesophagus. Another problem that happens sometimes is that the join where the oesophagus has been rebuilt can narrow down (called a stricture) and cause difficulties with feeding and swallowing. It is thought that strictures can be caused or made worse by reflux._x000D_ _x000D_ Some surgeons who look after babies with oesophageal atresia use a medication to suppress the acid produced by the stomach even if there are no symptoms of reflux. A major reason for this is to reduce the risk of strictures forming. Despite this being an apparently popular option (about half of babies with oesophageal atresia are treated with this medication) the evidence for using this medication is weak. In fact, some studies of babies with oesophageal atresia have actually found that strictures are more common in babies treated with acid suppression than in those who were not. In addition, there is some suggestion that taking the medicine can increase the chance of certain types of infection._x000D_ _x000D_ We want to answer the question, “Should babies born with oesophageal atresia all be treated routinely with antacid medication to reduce strictures?” To do this we are planning a two-phased study._x000D_ _x000D_ Firstly, we will assess the feasibility of the study. We will work with surgeons, other doctors looking after babies with oesophageal atresia, families of such babies and others who are involved in their care to explore what is important to them and whether they would be willing to take part in a trial where we test our question._x000D_ _x000D_ Secondly, the findings from this will then be used to design a trial where babies with oesophageal atresia are allocated at random to either being given acid suppressing medicine or not. This is called a randomised controlled trial and is considered the best way to answer clinical questions like this._x000D_ _x000D_ The trial will start with a pilot phase when babies are recruited to the trial at around the time of their initial surgery and we continue to talk to those families and see how they are finding being in the trial and what made them agree or not agree to taking part. This information will be used to improve the trial before we progress to a full-scale trial where babies are allocated at random to either routine anti-reflux medication or dummy medication. We will then follow them up for one year to see if they develop a stricture and require any further treatments to address difficulties with feeding or swallowing. We hope to involve all of the major paediatric surgical centres in the UK._x000D_ _x000D_ We intend to disseminate the results via a detailed report to the funder, articles in scientific journals, presentations to healthcare professionals, and also at the conference of TOFS (Tracheo-Oesophageal Fistula Support) a charity dedicated to improving the lives of all who were born with the TOF condition and a partner in this research.

Lay abstract: BACKGROUND: Babies born with oesophageal atresia (OA) are unable to feed unless they have a surgical intervention to join the two ends of the oesophagus. Following surgery, some surgeons prescribe prophylactic antacid medication believing that this will reduce the incidence of anastomotic stricture. There is no evidence to support this practice, indeed some evidence suggests it may be harmful._x000D_ RESEARCH QUESTION: In infants born with oesophageal atresia (Population), does the routine use of antacid medication (Intervention) compared to matched placebo (Comparator) impact the incidence or severity of anastomotic stricture (Outcome)?_x000D_ AIMS AND OBJECTIVES:_x000D_ (1) To undertake a mixed-methods feasibility study with clinicians and parents to explore acceptability of the proposed trial including aspects of trial design, care pathways and outcomes_x000D_ (2) Incorporating lessons learnt from the feasibility study, to subsequently undertake a multicentre pragmatic blinded randomised controlled trial (RCT) with internal pilot and integrated economic evaluation_x000D_ TARGET POPULATION: Newborn infants with oesophageal atresia and distal tracheo-oesophageal fistula undergoing surgical repair._x000D_ SETTING: Specialist NHS Neonatal Surgical Units in the UK._x000D_ HEALTH TECHNOLOGY BEING ASSESSED: Infants enrolled will received either routine antacid medication or placebo from day of surgical repair for one year._x000D_ MEASUREMENT OF COSTS AND OUTCOMES: The principal outcome measure of the feasibility phase will be acceptability of the trial protocol to parents and clinicians. Primary outcome for the RCT will be severity of stricture, defined as number of dilatations performed within 1 year of trial entry. Secondary outcomes (measured at timepoints up to 1 year) include incidence of stricture, and other directly related procedures, adverse events, presence of symptoms of gastro-oesophageal reflux, need for treatment of reflux, growth, oral intake, respiratory symptoms, episodes of infection, maternal quality of life and mortality. Integrated within the trial we will conduct an economic evaluation from an NHS and societal perspective._x000D_ SAMPLE SIZE: 200 infants for the RCT would have 90% power to detect an increase of at least 2.7 in the odds of reducing the number of dilatations per infant within 1 year of trial entry by one at 5% two-sided level of statistical significance._x000D_ PROJECT TIMETABLES AND RECRUITMENT RATE: Total duration 90 months: 9-month feasibility phase, followed by a 3-month period to finalise trial delivery plan. Internal RCT pilot will take place at all recruiting centres for 18 months. Total recruitment period: 60 months, with 12 months follow-up, followed by final analysis and dissemination (6 months)._x000D_ EXPERTISE IN TEAM: The team has extensive experience in the design and conduct of RCTs in surgery and in newborn infants, trial methodology, surgical expertise, statistical and health economic analysis, qualitative methods, feasibility studies involving children. The study is supported by a specialist perinatal CTU and has strong PPI involvement. Indeed, PPI have suggested the choice of primary outcome and perceive the study as a potential milestone in care of oesophageal atresia patients._x000D_ IMPACT AND DISSEMINATION: This trial will provide conclusive evidence concerning the efficacy of antacid medication at reducing incidence and severity of stricture following oesophageal atresia repair. We will disseminate via scientific and lay channels to maximise impact.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL