Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND Use of maintenance antibiotic therapy with the macrolide azithromycin is increasing in a number of chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD. METHODS The Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial was a multicentre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial done at 6 European PCD clinics (tertiary paediatric care centres and university hospitals in Denmark, Germany, Netherlands, Switzerland, and UK). Patients with a confirmed diagnosis of PCD, aged 7-50 years old, and predicted FEV1 greater than 40% were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 mg or 500 mg as tablets according to bodyweight (</≥ 40 kg) or identical placebo, three times a week for 6 months. The random allocation sequence was a permuted block randomisation, with a block size of four, generated by an external consultancy. Participants, investigators, and care providers were masked to treatment allocation. The primary endpoint was the number of respiratory exacerbations over 6 months. Analysis was by intention to treat. This study is registered in the EU Clinical Trials Register, EudraCT number 2013-004664-58. FINDINGS Between June 24, 2014, and Aug 23, 2016, 102 patients were screened, of whom 90 were randomly assigned to either azithromycin (n=49) or placebo (n=41). The study was ended without having included the planned number of participants due to recruitment difficulties. The mean number of respiratory exacerbations over 6 months was 0·75 (SD 1·12) in the azithromycin group compared with 1·62 (1·64) in the placebo group, and participants receiving azithromycin had significantly lower rate of exacerbations during the individual treatment periods (rate ratio 0·45 [95% CI 0·26-0·78]; p=0·004). Four serious adverse events were reported, occurring in one (2%) of 47 participants in the azithromycin group and in three (7%) of 41 participants in the placebo group. Loose stools or diarrhoea were more common in the azithromycin group than in the placebo group (11 [23%] vs two [5%]). INTERPRETATION This first multinational randomised controlled trial on pharmacotherapy in PCD showed that azithromycin maintenance therapy for 6 months was well tolerated and halved the rate of respiratory exacerbations. Azithromycin maintenance therapy is an option for patients with PCD with frequent exacerbations potentially leading to reduced need for additional antibiotic treatments and preventing irreversible lung damage. FUNDING European Commission Seventh Framework Programme and Children's Lung Foundation (Denmark)

Nationwide lung function monitoring from infancy in newborn-screened children with cystic fibrosis

Background Cystic fibrosis (CF) lung disease starts in infancy and can be assessed for structural lung abnormalities using computed tomography or magnetic resonance scans, or for lung function impairment using multiple breath washout (MBW). However, in infancy these two methods are not well correlated. Trajectories of CF lung disease assessed by MBW in infants and toddlers remain poorly described, which is why we aimed to 1) describe the trajectory of lung function, 2) explore risk factors for progression and 3) explore the real-life effect of lumacaftor/ivacaftor. Methods This was a nationwide observational cohort study (2018–2021) using data collected as part of the routine clinical surveillance programme (including MBW and monthly endo-laryngeal suction sampling for bacterial pathogens) in children born after implementation of newborn screening for CF (May 2016). Lumacaftor/ivacaftor commenced from age 2 years in children homozygous for F508del. Ventilation distribution efficiency (VDE), recently described to have advantages over lung clearance index (LCI), was reported as the primary MBW outcome after z-score calculations based on published reference data. Mixed effect linear regression models were the main statistical analyses performed in this study. Results 59 children, aged 2–45 months, contributed with 211 MBW occasions (median (interquartile range (IQR)) 3 (2–5) MBW occasions per child) with a median (IQR) follow-up time of 10.8 (5.2–22.3) months. An overall mean annual deterioration rate of −0.50 (95% CI −0.78– −0.22) z-VDE was observed, starting from an estimated mean z-VDE of −1.68 (95% CI −2.15– −1.22) at age 0.0 years (intercept). Pseudomonas aeruginosa “ever” (n=14, MBWs 50) had a significantly worse z-VDE trajectory versus P. aeruginosa “never” (mean difference 0.53 (95% CI 0.16–0.89) per year; p=0.0047) and lumacaftor/ivacaftor treatment (n=22, MBWs 46) significantly improved the trajectory of z-VDE (mean difference 1.72 (95% CI 0.79–2.66) per year; p=0.0004), leading to a stable mean z-VDE trajectory after start of treatment. Conclusions Infants and toddlers with CF demonstrated progressive deterioration in z-VDE over the first years of life. P. aeruginosa isolation “ever” was associated with an accelerated deterioration in lung function, while lumacaftor/ivacaftor therapy significantly improved and stabilised the trajectory