Bacterial Lysate In Preventing Asthma (BLIPA)

Oral Bacterial Lysate to Prevent Persistent Wheeze in Infants After Severe Bronchiolitis; a Randomised Placebo-controlled Trial

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. BLIPA is a phase 2b, randomised, double blind, placebo-controlled study, investigating the efficacy superiority of bacterial lysate (Broncho Vaxom) capsules over placebo, in reducing wheeze in infants after severe bronchiolitis. The primary end point of the study is parent-reported, healthcare-professional confirmed wheeze at 19-24 months. The study aims to test bacterial lysate capsules (3.5mg over 24 months) for safety, efficacy, and to advance mechanistic understanding of its action.

The BLIPA study aims to investigate the following research questions: In children hospitalised with bronchiolitis, does oral Broncho Vaxom (BV) given for 10 days per month for a total of 24 months, prevent parent-reported, healthcare professional-confirmed, wheeze between 19 and 24 months post initiation of IMP/placebo. Does oral BV reduces the risk of wheeze after bronchiolitis by modulating T cell and Dendritic cells (DC) maturation and altering the gut and airway microbiota. (mechanistic hypothesis) The BLIPA study will combine the results of two multi-centre, randomised trials with similar but separate protocols: BLIPA-United Kingdom (UK), with recruitment in London, Southampton, Edinburgh, and Aberdeen and BLIPA-Australia, with recruitment in Brisbane, Gold Coast, Melbourne, Darwin and Sydney. BLIPA-UK is funded in the UK by the NIHR (National Institute for Health and Care Research). BLIPA-Australia is funded in Australia by the International Clinical Trial Collaboration (ICTC). ICTC supports Australian researchers to conduct clinical trial research in collaboration with international researchers. The total study duration is 54 months. The primary clinical objective is to recruit a population of eligible participants, to randomise them to oral Broncho Vaxom (3.5mg) or placebo, to be taken daily for 10 days a month over 24 months, follow up for 24 months and compare primary and secondary outcomes between trial arms. Parents or guardians of children, clinicians involved in their care and trial staff will be blinded to the treatment arm. Recruitment will be for 18 months and children's outcomes will be assessed for 24 months following initiation of Investigational Medicinal Product (IMP) or placebo. Within six weeks of hospital discharge following admission for bronchiolitis, parents or guardians can consent to their child partaking in the study, baseline data is collected, the child is randomised, and the IMP or placebo is initiated (12 months' supply). From the point of treatment initiation, children are followed up for 24 months, the same length as the treatment period. There will be at least one scheduled face to face visit at 12 months to dispense a further year's supply of IMP or placebo.

Children will be allocated into two arms (oral BV and placebo) in a 1:1 ratio. Randomisation will be stratified by site and parental asthma and the lists generated using random blocks of size 4 and 6.

Parents or guardians will be blind to treatment allocation, as will the entire site study team involved in the management of the study, including the Chief Investigator (CI), PIs, sub-investigators, study nurses, and site coordinators. Trial Steering Committee (TSC) members will remain blind. The progress and safety of the study will be assessed by the Data Monitoring Committee (DMC). The DMC will therefore not be blinded. The main study trial manager (PCTU) and trial monitors will be blinded. The Sponsor's Joint Research Management Office (JRMO) including the JRMO monitor(s) will unblind themselves to specific patients in order to report SUSARs to the Medicines and Healthcare products Regulatory Agency (MHRA). The study pharmacist will be blinded, and the study pharmacy file will contain blinded documents, please see pharmacy manual. The treatment allocation list will be available from the PCTU or their designate (Sealed Envelope) on request should the need arise.

Bacterial lysate medicines are made from bacterial cells that are broken down and are intended to stimulate the immune system.

Parent or guardian reported wheeze between 19-24 months that is also confirmed by the presence of one or more of the following in the primary care record: salbutamol inhaler, active wheeze diagnosis, asthma diagnosis.

Number of prescriptions for salbutamol inhalers as recorded on the primary care record between 19-24 months

The time to first episode of parent-reported wheeze during the 24 months since initiation of study drug

Number of courses of systemic corticosteroids for wheeze during the 24 months since initiation of study drug

Number of courses of systemic corticosteroids for wheeze during the 24 months since initiation of study drug

Presence of a prescription for regular oral montelukast recorded in the primary care record between 19-24 months.

Presence of eczema between 19-24 months confirmed by parent report at study follow ups (parent reported outcome)

Presence of Eczema confirmed by U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. between 19-24 months.

Incidence of Suspected unexpected serious adverse reactions (SUSARs) for the treatment group between 0-24 months

Incidence of Suspected unexpected serious adverse reactions (SUSARs) for the treatment group between 19-24 months

Inclusion Criteria: Parent/Guardian able to provide written informed consent Within 6 weeks of discharge from hospital for bronchiolitis Child aged 3-12 months at the time of consent to study A diagnosis of Bronchiolitis requiring a hospital admission (defined as more than 4 hours in hospital) Contactable for regular follow up by the research team Exclusion Criteria: Any previous hospital attendance for bronchiolitis More than one episode of healthcare professional-diagnosed wheeze prior to index bronchiolitis episode Premature gestational age less than 37 weeks Any severe chronic condition such as cystic fibrosis, sickle cell disease, severe developmental delay, immunodeficiency, or anything that has a significant impact on the respiratory tract (such as need for non-invasive ventilation) or increases vulnerability to respiratory tract infections. History of clinically significant neonatal disease (e.g. neonatal pneumonia, congenital lung abnormality, neonatal chronic lung disease) Genetic conditions that affect the immune system (e.g. Down's syndrome/Trisomy 21) Current regular oral montelukast or inhaled corticosteroid therapy or inhaled salbutamol therapy Current regular treatment with immunomodulatory drugs (e.g oral steroids) Known allergy or previous intolerance to study medication. Currently enrolled to another Randomised Clinical Trial. (Unless prior approval is given by Principal Investigator) Sibling of a BLIPA participant (of the same household or family)