Children with neurological impairment (NI) are at high risk of lower respiratory tract infections (LRTI), often leading to repeated hospitalisations. This places a huge burden on children, their families and healthcare services. To prevent LRTIs, some children are prescribed prophylactic antibiotics. However, this practice is variable and based on very limited evidence. Furthermore, these medications are not without side-effects. Also, there are increasing concerns about risks associated with their long-term use, particularly the development of antimicrobial resistance. Our international, multi-centre placebo-controlled trial involving ~40 UK and 4 Australian sites aims to determine whether long-term use (52-weeks) of azithromycin compared to placebo reduces LRTI-related hospitalisations in 474 children with non-progressive NI. We will also assess whether antibiotic prophylaxis reduces healthcare utilisation and improves quality of life (for both parent and child/adolescent), whilst not adversely influencing respiratory tract microbiology or causing adverse events/side effects. Our study results will inform clinical practice and national/ international guidance for this patient group.