Title: Oral bacterial lysate to prevent persistent wheeze in infants after severe bronchiolitis; a randomised placebo controlled trial (BLIPA; Bacterial Lysate in Preventing Asthma)
Funder: Medical Research Council

Abstract: What is the problem?_x000D_ Young children who develop wheeze are at an increased risk of developing lifelong asthma. Preventing the development of wheeze in preschool children would produce major health benefits, but to date no therapies have proved to be effective._x000D_ _x000D_ Which children are at high risk of developing asthma?_x000D_ A group of infants who are at very high risk of developing preschool wheeze and subsequent asthma, are infants who are admitted to hospital with breathing problems due to a viral infection of their small breathing tubes. Since these small breathing tubes are called bronchioles, the disease is called bronchiolitis. Current thinking is that bronchiolitis does not cause asthma, but that infants with severe bronchiolitis have an underlying vulnerability in their immune system that increases the risk of developing both bronchiolitis and asthma. _x000D_ _x000D_ Why do we need this study?_x000D_ One way of boosting the immune system in order to prevent chest infections in infants is to give granules of broken up (lysed) dead bacteria. This therapy, called Broncho Vaxom, has been safely used in infants for many years in continental Europe. Recently, studies in animal models suggest that oral Broncho Vaxom also has the potential to prevent the development of wheeze after severe bronchiolitis. We therefore propose, to test whether this protective effect for wheeze seen in these animal models also applies to human infants._x000D_ _x000D_ What do we aim to do?_x000D_ We will recruit infants admitted to hospital with bronchiolitis. Infants will be given oral Broncho Vaxom or an identical dummy medicine for the first 10 days in each month for a total of 24 months. Every month, parents will be contacted by phone or text and episodes of wheeze recorded. The main (primary) aim of the trial is to detect a reduction in parent-reported, and doctor-confirmed, wheeze between 18 and 24 months in children treated with Broncho Vaxom._x000D_ _x000D_ What is the main question we want to address?_x000D_ Does Broncho Vaxom prevent the development of wheeze after bronchiolitis, and what mechanisms could be involved?_x000D_ _x000D_ What sort of study do we propose?_x000D_ We will perform a multi-centre, randomised, placebo-controlled trial. This means that parents and researchers do not know which children are given active or inactive treatment, and infants will be assigned to treatment by chance. _x000D_ _x000D_ What active medicine will be given to infants?_x000D_ Broncho Vaxom is an oral medication that parents will give to their children mixed with a drink or with food once a day for the first 10 days of each month for 24 months._x000D_ _x000D_ What inactive medicine will we give?_x000D_ We will give a “dummy” inactive medicine (called a placebo) that has the same appearance and taste as oral Broncho Vaxom granules, for 10 days a month for a total of 24 months._x000D_ _x000D_ Who will we study?_x000D_ We will recruit infants aged 3 to 12 months, admitted to hospital with bronchiolitis. To detect a 40% reduction in wheeze, and allowing for 15% of infants dropping out, we will need to recruit 894 infants._x000D_ _x000D_ Does this trial represent value for money?_x000D_ Prevention of asthma has the potential to deliver major cost savings. Prevention of post-bronchiolitis wheeze could prevent up to 78,000 new cases of asthma._x000D_ _x000D_ How have we involved parents?_x000D_ Parents reviewed and commented on the trial’s design. For the trial, parents of children with bronchiolitis will advise the researchers, and will be invited to become members of the trial management committees

Lay abstract: Research question_x000D_ In infants hospitalised with bronchiolitis, does oral Broncho Vaxom (BV; a lysate of respiratory bacteria), given for 10 days per month for a total of 24 months, prevent parent-reported, doctor-confirmed, wheeze at 18 to 24 months post hospital admission?_x000D_ _x000D_ The mechanistic question to be addressed is whether BV therapy alters systemic T regulatory and dendritic cells, and increases the diversity of the gut and upper airway microbiota._x000D_ _x000D_ Background_x000D_ Bronchiolitis is a common viral infection of the small airways of infants and some affected infants will require hospital admission. Severe bronchiolitis is a marker for greatly increased risk of developing both preschool wheeze and subsequent school age asthma. Since epidemiological studies suggest that exposure to microbial products protects against preschool wheeze, lysates of bacteria may prevent the development of wheeze after bronchiolitis, with long-term beneficial consequences. _x000D_ _x000D_ Aims and objectives_x000D_ 1) To test whether oral BV prevents parent-reported doctor-confirmed wheeze in infants after severe bronchiolitis._x000D_ _x000D_ 2) To describe the effect of 24 months of oral BV treatment on markers of systemic T cell and dendritic cell maturation, and on the diversity of the microbiota in the upper airway and gut._x000D_ _x000D_ Methods_x000D_ Infants aged 3 to 12 months admitted to hospital with bronchiolitis will be randomly allocated to receive either oral BV 3.5 mg or placebo 10 days a month for 24 months. Trial therapy will be initiated within 4 weeks of hospital discharge. Parents will be contacted every month for presence of wheeze, wheeze therapy, and unscheduled need to medical attention for wheeze. The trial’s primary outcome will be parent-reported and doctor-confirmed wheeze between 18 and 24 months. _x000D_ _x000D_ A sample size of 894 infants will provide 90% power, with a Type 1 error rate of 5%, and allowing for 13% dropouts, to detect a 40% reduction in active wheeze between 16 and 24 months. This is a recruitment rate of 31%. _x000D_ _x000D_ The effect of BV on mechanisms for wheeze development will be assessed in the subgroup of infants recruited at the Royal London Hospital. Nasopharyngeal swabs and stool samples for microbiota will be obtained at trial entry and at 24 months, and markers of maturation of systemic T regulatory and dendritic cells, and serum immunoglobulin E, will be assessed at 24 months. _x000D_ _x000D_ Timelines for delivery_x000D_ The trial started in January 2021 with regulatory approvals obtained in November 2021. Recruitment of infants will cover 2 winter seasons (2021 and 2022). Data acquisition will end in March 2025 and the trial will end in June 2025._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ We will disseminate our results via the peer-reviewed literature and via our extensive links with the media. If the study shows that BV therapy prevents wheeze development, it has the potential to produce significant health benefits. This is because 13% of all cases of asthma in children are associated with previous history of bronchiolitis. If the study is negative, it is of sufficient power to be regarded by the paediatric community to be a definitive result.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: RESPIRATORY