Project overview
Research question. Can three years of house dust mite sublingual immunotherapy, given to infants at high risk of developing asthma, prevent the development of atopic recurrent wheeze (ARW, a surrogate end-point for asthma)? Background. Asthma is the most common chronic disease of childhood. As yet, there is no effective strategy to prevent the development of asthma. The trajectory of asthma is established very early in life. In children with atopic heredity, persistent Th2 immune-response lead to risk of asthma development. Reducing HDM exposure early in life may augment rather than reduce sensitisation. In order to counter allergen-specific Th2 bias, strong immune stimulation such as administration of house dust mite (HDM) allergen, is required. We proposed that prophylactic HDM sublingual immunotherapy (HDM-SLIT) has the potential to block early Th2 polarisation that primes children to develop asthma. We conducted the first randomised, double-blind, placebo-controlled trial of prophylactic administration of HDM extract as a proof of concept study. In 111 infants at high risk of asthma, administration of sublingual HDM extract for 1-year resulted in consistent reduction in allergen sensitisation, and a 5-fold reduction in asthma at 6-years. Importantly, the intervention was safe with no difference in adverse effects between HDM and placebo groups. Aims and objectives. We now propose an adequately powered, multicentre trial to obtain definite proof of efficacy in a study group that represents the wider UK population. Primary objective is to establish efficacy of HDM-SLIT tablet in preventing the development of ARW (recurrent wheeze plus allergic sensitisation) at 3.5-4 years. Secondary objectives include assessment of safety, preventive effect on other allergic conditions, and understanding the humoral and cellular immune responses to prophylactic allergen immunotherapy (AIT). Methods. We will recruit 434 infants, aged 6 to 12 months, at high risk of asthma and randomise them (1:1 ratio) to HDM-SLIT (n=217) or placebo (n=217) for 3 years. HDM-SLIT (30 µg protein) will be given as sublingual, immediately dissolvable, tablet formulation to achieve optimal immune modulation. Primary outcome: proportion of infants who develop ARW in the active group compared to the placebo group after 3 years of treatment. Infants will be assessed at 6 weekly telephone/virtual visits in the first year and 3 monthly visits in year 2-3 years to evaluate allergic symptoms and adverse events and to promote adherence. Three annual visits over the duration of treatment will be conducted and include asthma/allergy questionnaires and skin prick testing. Lung function and exhaled nitric oxide will be performed at the last visit (3½ to 4 years of age). Blood and nasal sampling will be carried out at baseline and last visit for mechanistic studies. Timelines for delivery (months). (i) 0-6: Study set-up, (ii) 7-30: Recruitment, (iii) 7-66: Follow-up, (iv) 67-72: Analyse, study report/publication, dissemination. Anticipated impact and dissemination. Effective prevention strategies can help alleviate societal and economic burden of asthma in the community, improving children's quality of life and reduce the need for health care resources. Dissemination will be guided by our PPI group and partner asthma charities. Working with the NIHR Dissemination Centre, we will disseminate study result widely to the scientific community as well as to the general public.
