ISRCTN71955516.

Study name	Joint UK and Australia multicentre, randomised, double‐blind, placebo‐controlled pragmatic trial comparing 52 weeks of azithromycin to placebo in children with neurological impairment at risk of lower respiratory tract infection (the PARROT trial)
Methods	Randomised Controlled Trial  Randomised participants will receive 52 weeks of treatment with either azithromycin or placebo, randomised in a 1:1 ratio. Both participants and their healthcare teams will be blinded to treatment allocation.  All participants will be followed up for 52 weeks from randomisation. If trial recruitment is ongoing at 78 weeks, participants will also be followed up at this time point.
Participants	Inclusion criteria Children and young people who are aged between 3 and 17 years (inclusive) at randomisation Written informed consent from participant (or appropriate person if incapacitated/minor) Participant (or appropriate person if incapacitated/underage) and caregiver have a good understanding of the English language Diagnosed with non‐progressive, non‐neuromuscular neurological impairment* Persistent respiratory symptoms** One or more of the following: received at least 2 courses of oral antibiotics for LRTI in 52 weeks prior to eligibility have been hospitalised with a LRTI within 52 weeks prior to eligibility and completed 13‐week ‘washout’ period (where applicable)*** prescribed prophylactic antibiotics for LRTIs and undergone a 13 week ‘washout’ period***. * Most will likely have cerebral palsy. However, some children may have no formal diagnosis to account for their symptoms. ** Persistent respiratory symptoms defined by LRSQ‐Neuro score of >= 95% CI for age. *** Must have undergone a 13‐week ‘washout’ period where administered IV antibiotics during hospitalisation or have been previously prescribed and administered prophylactic or nebulised antibiotics. Exclusion criteria Any neuromuscular disorders including spinal muscular atrophy (SMA), Duchenne muscular dystrophy etc., or neurological disorders in which progressive deterioration in neurological condition are known to occur (e.g. Rett syndrome, some neurometabolic syndromes) Pre‐existing non‐neurological conditions that impact respiratory functions such as cystic fibrosis (CF), immunodeficiency etc. Note: Children with neurological impairment known to have bronchiectasis will not be excluded Known contra‐indication to using or hypersensitivity to: azithromycin, erythromycin, macrolide or ketolide antibiotic, or to any of the excipients contained in the study drug Use of macrolide antibiotics within 90 days prior to eligibility  Known significant hepatic disease (hepatic impairment per Child‐Pugh classification C) Treatment with ergot derivatives (dihydroergocristine, dihydroergotamine, dihydroergotoxine, nicergoline or a combination of dihydroergocryptine with caffeine) Child/young person already taking prophylactic antibiotics for non‐respiratory causes (e.g. urinary tract infections) Previously randomised in PARROT Recruited to another IMP trial and continuing to administer the IMP
Interventions	Intervention  Powder formulation of azithromycin reconstituted and administered as an oral suspension. The dosing regimen will be based on body weight (10 mg/kg rounded) and will be given 3 times a week (Mon/Wed/Fri). Control  Matched reconstituted powder formulation of placebo.
Outcomes	Primary Outcome Measure Proportion of children and young people (3 to 17 years) hospitalised at their recruiting or designated centre with LTRI over the 52‐week intervention period, recorded at 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks. Secondary Outcome Measures Health‐related QoL of child and parent/carer measured using parent QoL assessment (Warwick‐Edinburgh Mental Wellbeing Scale) and patient QoL assessment (DISABKIDS) at baseline, 13, 26, 39 and 52 weeks. Safety events, tolerability and adherence measured by the assessment of adverse events and withdrawals from study treatment at 4, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks, and treatment diary at 13, 26, 39 and 52 weeks. Respiratory medication usage assessed by reviewing concomitant medication which could impact the respiratory system at baseline, 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks, and vaccinations at baseline and 52 weeks. Weight based on World Health Organisation Z‐scores using WHO Anthro calculator (www.who.int/growthref/tools/en), assessed at baseline, 13, 26, 39 and 52 weeks. Quality/amount of parent and child/young person’s sleep, measured using the primary caregiver sleep actigraphy and corresponding primary caregiver sleep log (UK only), the Child’s Sleep Habits Questionnaire and 1‐week patient sleep diary, at baseline and 52 weeks. Respiratory symptoms measured using LRSQ‐Neuro score and the respiratory symptom questionnaire at baseline, 13, 26, 39 and 52 weeks, and changes to respiratory treatments/support and surgical/other interventions at 13, 26, 39 and 52 weeks. Number, duration and severity of LRTI; time to first LRTI is measured by reviewing the occurrence of chest infection and LRTI, changes to respiratory treatments/support and the assessment of adverse events at 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks; by using the resource use questionnaire at baseline, 13, 26, 39 and 52 weeks and documenting length of stay in hospital, admission to critical care and changes to respiratory treatments/support for any unscheduled visits. Unscheduled medical presentations (general practice visits and emergency department attendances) for LRTI measured by reviewing medical history at baseline; reviewing the occurrence of chest infections and LRTIs and the assessment of adverse events at 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks, and using the resource use questionnaire at baseline, 13, 26, 39 and 52 weeks. Use of other health and social care services, school attendance and indirect costs measured using the resource use questionnaire at baseline, 13, 26, 39 and 52 weeks and Hospital Episode Statistics (HES) at 52 weeks. Number of courses of ‘rescue’ antibiotics prescribed for LRTI measured by reviewing concomitant medications which could impact the respiratory system at baseline, 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks. Quality‐adjusted life years (QALY) measured using CHU9D and EQ‐5D‐Y at baseline, 13, 26, 39 and 52 weeks. Nasal swab for microbiology and resistance profiling taken at baseline, 26 and 52 weeks, and for unscheduled visits (for Australian participants only until UK contractual arrangements are in place). Nasal swab/nasopharyngeal aspirate to investigate viral causes of acute LRTI (as defined by the protocol) and cough swab/sputum collection to investigate bacterial causes of acute LRTI (as defined by the protocol) taken at unscheduled visits (for Australian participants only until UK contractual arrangements are in place). Residual impact of 52 weeks' antibiotic prophylaxis assessed at 78 weeks, using the following measures: respiratory symptoms measured by assessing LRSQ‐Neuro score, respiratory symptom questionnaire, changes to respiratory treatments/support and surgical and other interventions weight based on World Health Organisation Z‐scores using WHO Anthro calculator (www.who.int/growthref/tools/en) nasal swab for microbiology and resistance profiling changes in respiratory medication usage measured by reviewing concomitant medications which could impact the respiratory system and vaccinations number, duration and severity of LRTI; time to first LRTI measured using the resource use questionnaire and reviewing the occurrence of chest infection and LRTI, changes to respiratory treatments/support and the collection of adverse events QALY measured using the CHU9D and EQ‐5D‐Y use of other health and social care services, school attendance and indirect costs measured using HES health‐related QoL of child and parent/carer measured using the patient QoL assessment (DISABKIDS) and parent QoL assessment (Warwick‐Edinburgh Mental Well‐being Scale) unscheduled medical presentations (GP visits and A&E attendances) for LRTI measured by reviewing the occurrence of chest infection and LRTI, the collection of adverse events and the resource use questionnaire number of courses of ‘rescue’ antibiotics prescribed for LRTI measured by reviewing concomitant medications which could impact the respiratory system safety events measured using the assessment of adverse events
Starting date	1 March 2019
Contact information	Helen Eccleson parrot@liverpool.ac.uk
Notes

Abbreviations: IMP: investigation medical product; IV: intravenous; LRSQ: Liverpool Respiratory Symptom Questionnaire; LRTI: lower respiratory tract infection; QoL: quality of life;

If results of this trial are appropriate for inclusion in future reviews, it will be important to avoid overestimating the treatment effect due double counting participants from PARROT and PARROT‐Junior in the analysis.