Rationale: Modulator therapies like ivacaftor have revolutionized clinical management of cystic fibrosis, showing marked short-term benefits in trials but heterogeneous findings in long-term observational studies. Since newer modulators have become the standard of care for the majority living with cystic fibrosis in the United States, characterizing long-term effectiveness with real-world data is increasingly difficult because of the lack of contemporary comparator groups for performing between-subjects analyses.Objectives: To determine the extent to which ivacaftor preserves long-term lung function and compare the results of within- and between-subjects analyses for evaluating its real-world effectiveness.Methods: This retrospective cohort study used data from the U.S. Cystic Fibrosis Foundation Patient Registry (2003-2016). We used two approaches to evaluate ivacaftor effectiveness on percent predicted forced expiratory volume in 1 second (ppFEV1): 1) within-subject comparisons of ppFEV1 before and after ivacaftor initiation; and 2) comparisons between ivacaftor-treated and untreated individuals with similar disease pathology. We modeled data from 560 ivacaftor-treated individuals with the G551D variant. For between-subjects comparisons, we used propensity scores to match the treated group with 2,800 untreated F508del homozygous individuals. Modulator initiation bias was assessed and accounted for in each model.Results: Our results showed an initial average improvement in ppFEV1 in ivacaftor-treated children and adults (ranging from 4.54% to 6.53% predicted based on within-subject comparison of before vs. after ivacaftor initiation). There was a slower decline in adults, compared with children. These ivacaftor-treated cohorts experienced less decline relative to their F508del homozygous counterparts (between-group differences in treated vs. control ranged from 0.36% to 0.64% predicted). Both the within- and between-subjects comparisons demonstrated similar degrees of ivacaftor effectiveness. However, small differences between the two approaches were observed in younger individuals.Conclusions: Ivacaftor was associated with improved ppFEV1 across all age groups, with the magnitude of improvement roughly 50% of that observed in clinical trials. The results support the need to account for modulator initiation bias and the use of within-subject analysis in future CFTR (cystic fibrosis transmembrane conductance regulator) modulator effectiveness studies, but caution is advised in younger individuals because of developmental changes that may affect pre- and post-treatment comparability.

Abstract Background Elexacaftor-tezacaftor-ivacaftor (ETI) has been demonstrated to improve lung function in clinical trials; however, evidence describing effects on trajectories and whether long-term improvements are sustained (>1-year) is lacking. We estimated within-person lung clearance index (LCI) trajectories before and after ETI initiation, assessing changes in level and rate of change, alongside acute LCI change, up to three years after ETI initiation. Methods Prospective observational study of children at a tertiary hospital. Children aged 3–17 years with ≥2 LCI testing occasions (i) before and (ii) after starting ETI were used to describe lung function trajectories. Children with ≥1 pre-ETI and ≥1 post-ETI LCI occasion(s) were used to describe acute LCI change after ETI initiation. Age-adjusted LCI trajectories for time periods (i) before and (ii) after ETI initiation were estimated using linear mixed-effects models, and pre- and post-ETI LCIs were compared using paired Wilcoxon tests. Results Mean pre-ETI and post-ETI longitudinal changes in LCI were -0.007 (95% CI: -0.28, 0.27; n=35) and 0.12 (95% CI: -0.17, 0.41; n=20) turnovers per year, respectively. Before ETI initiation, 57% (30/53) of patients had an LCI≥7.1 turnovers (indicating impaired lung function), compared to 26% (14/53) post-ETI, with a median LCI difference of -0.70 (95% CI -0.84, -0.46; p<0.001) turnovers. Within-individual variability in LCI decreased post-ETI. Conclusions Our real-world data within a unique longitudinal study provide a comprehensive picture of ETI benefit by outlining not only acute improvement in LCI but maintained stability in LCI trajectories and improved LCI stability sustained up to three years post-initiation.

Background Gut dysbiosis is a hallmark of cystic fibrosis (CF), typically characterised using non-specific diversity metrics and study-specific taxonomic lists, limiting comparability across studies. We aimed to develop a metagenomic, species-level CF Gut Microbial Dysbiosis Index (CF-GMDI) to standardise measurement of gut microbial imbalance in children with CF (cwCF) Methods CF-GMDI was derived using stool metagenomic data from the PEARL-CF study (70 cwCF; 67 healthy controls (HC); 0-6 years). Differentially abundant taxa were identified between cwCF and HC using MaAsLin2. The index was calculated as the log10 ratio of the summed relative abundances of taxa enriched in CF vs HC to those depleted in CF vs HC. Reproducibility was assessed in the independent EARTH cohort (56 cwCF; 56 HC; 0-18 years). Responsiveness to therapy was evaluated using publicly available metagenomic data from an Elexacaftor/Tezacaftor/Ivacaftor (ETI) study (39 cwCF; 6-18 years). Results CF-GMDI was significantly higher in cwCF than HC (p < 0.001), inversely correlated with species richness (ρ = -0.74, p < 0.001), and higher in pancreatic-insufficient vs pancreatic-sufficient cwCF in the PEARL-CF cohort (p = 0.01). Key ecological and clinical associations were replicated in the EARTH cohort. In the ETI study, CF-GMDI decreased significantly at 6 and 12 months post-treatment, whereas alpha diversity remained unchanged. Conclusions CF-GMDI is a CF-associated metric that captures clinically relevant gut microbiome restructuring not detected by standard diversity measures in cwCF (0-18 years). It differentiates disease and pancreatic status and tracks therapeutic modulation, supporting its use as a novel endpoint in CF intervention studies.

Non-tuberculous mycobacteria (NTM) represent a significant disease burden in the cystic fibrosis (CF) population. Whilst the acquisition of NTM to the respiratory tract is predominantly attributed to environmental exposures, the contribution of the gut-lung axis to NTM pulmonary disease remains poorly understood. In this study, we retrospectively examined 1285 stool microbiomes from 121 children and 52 adults with CF, and 135 healthy control (HC) children, in order to assess the prevalence, abundance and clinical significance of NTM in the gut. We detected various species of low clinical concern in the stool of 2% of people with CF and 1% of HC sampled, with longitudinal sampling revealing their occurrence to be sporadic and transient. Of the participants studied, only 11 had a history of prior clinical NTM respiratory colonisation or infection, but there was limited evidence to support ongoing persistence in the intestinal tract. This study suggests that the gut is not a meaningful reservoir for pulmonary NTM infections and it is unlikely to serve as a transmission route within the CF population.

BACKGROUND:People with cystic fibrosis can have impaired insulin secretion and hyperglycaemia before meeting the diagnostic criteria for cystic fibrosis-related diabetes during an oral glucose tolerance test (OGTT). Insulin therapy given to such patients was associated with improved weight and lung function in several small, uncontrolled trials but might increase treatment burden and cause hypoglycaemia. We aimed to assess whether insulin treatment improves weight and lung function when given to patients with cystic fibrosis with early glycaemic abnormality. METHODS:CF-IDEA was a multicentre, randomised controlled trial conducted at five children's hospitals in Australia and one in the USA. Eligible participants were children with cystic fibrosis aged 5-18 years without cystic fibrosis-related diabetes and with peak glucose concentration on a five-point OGTT of 8·2-11·0 mmol/L (cystic fibrosis insulin deficiency stage 1) or ≥11·1 mmol/L (cystic fibrosis insulin deficiency stage 2). Participants were randomly assigned (1:1) to insulin or observation. Randomisation was done using the biased coin method, followed by minimisation when the study groups became imbalanced by chance. Randomisation was stratified by glycaemic category (cystic fibrosis insulin deficiency stage 1 or 2), weight Z score (more than or equal to -0·61 or less than -0·61), and study centre. Participants in the insulin group received once-daily, long-acting insulin detemir by subcutaneous injection before breakfast, commencing at 0·1 units per kg per day, adjusted in 0·5-unit increments to achieve all fingerstick blood glucose concentrations between 4 mmol/L and 8 mmol/L. The primary outcomes were absolute changes in weight Z score, percentage predicted forced expiratory volume in 1 s (ppFEV1), and percentage predicted forced vital capacity (ppFVC), derived with generalised estimating equations and presented with two-sided 95% CIs. Severe hypoglycaemic events (defined as requiring outside assistance or causing reduced level of consciousness or seizure), insulin-related adverse events, and continuous glucose monitoring (CGM) percentage time with blood glucose below 3·9 mmol/L were recorded as safety outcomes. This study is registered with ClinicalTrials.gov, NCT01100892, and is completed. FINDINGS:Between Dec 6, 2010, and Feb 25, 2022, 109 participants were randomly assigned to observation (n=54) or insulin (n=55). Five participants withdrew after the baseline visit, and the analysis therefore included 104 participants (53 observation and 51 insulin); 95 participants completed the 12-month protocol and nine completed only 6 months. Baseline characteristics were similar between the groups; however, the observation group included 30 (57%) boys and 23 (43%) girls, whereas the insulin group included 23 (45%) boys and 28 (55%) girls. The median daily insulin dose at 12 months was 0·12 units per kg per day (range 0·05-0·41). There were no statistically or clinically significant differences between the observation and insulin groups in change in weight Z score (difference insulin minus observation 0·07 [95% CI -0·04 to 0·18]; p=0·20), change in ppFEV1 (1·2 [-2·2 to 4·7]; p=0·48), or change in ppFVC (0·6 [-2·6 to 3·8]; p=0·72). Similarly, there were no significant differences in subgroup analyses by cystic fibrosis insulin deficiency stages 1 and 2. There were no episodes of severe hypoglycaemia or insulin-related adverse events, and we found no evidence of difference between the observation and insulin groups in CGM percentage time less than 3·9 mmol/L. INTERPRETATION:Insulin treatment did not improve weight or lung function when given to children and adolescents with cystic fibrosis and early glycaemic abnormalities. Insulin treatment should not be given to those who do not meet OGTT criteria for cystic fibrosis-related diabetes. FUNDING:National Health and Medical Research Council of Australia, Australian Cystic Fibrosis Research Trust, Pfizer Australasian Paediatric Endocrine Care Research Grant, Novo Nordisk Regional Diabetes Support Scheme, Sydney Children's Hospital Foundation.

INTRODUCTION:Infection is a primary cause of progressive pulmonary disease in people with cystic fibrosis (pwCF). Researchers frequently utilize data registries or centre-based cohort studies to study infections in CF. We examine challenges encountered in conducting two multi-centre non-interventional investigator-led cohort studies undertaken a decade apart. METHODS:The Australian Clonal Pseudomonas Study (ACPinCF, 1294 participants) and the National NTM in CF study (1314 participants) leveraged clinical practice, with data was supplied by clinics and the Australian CF Data Registry. Diagnostic laboratories performed cultures according to local protocols. RESULTS:Site approval times were lengthy; 16 months for the ACPinCF study and between 21-44 months for the National NTM in CF study. The latter required individual contract negotiation with each clinical site as a requirement of governance approval. Changing clinical demands and unforeseen challenges such as the SARS-CoV-2 pandemic significantly impacted the NTM study. Despite these challenges, participant retention remained robust, with minimal loss to follow-up. Changes in CF centre leadership and health service policy on cost-recovery for research participation further exacerbates the challenges of maintaining longitudinal cohort CF studies. CONCLUSIONS:Conducting and sustaining longitudinal non-interventional studies present significant challenges. Even after costs for centre participation, sample processing, data curation, data analysis and results output are covered by grant funding, these studies will still heavily depend on significant support provided by the centres without substantial funding.

The role of probiotics in children with cystic fibrosis (CwCF) remains unclear. The PEARL-CF study was an international, double-blind, randomized, placebo-controlled study involving CwCF (0–6 years), and assessed the effects of a probiotic on intestinal microbiota and clinical outcomes. A multi-strain probiotic (15 Lactobacillus/Bifidobacterium strains; ∼2-3×10 10 CFU daily) or placebo was administered for 12-months and participants followed a further 12-months post-intervention. Among 77 CwCF (38 probiotic, 39 placebo), bacterial alpha diversity did not differ between groups. Participants ≥4 years on probiotic demonstrated higher bacterial richness (post-hoc analysis). Haemophilus influenzae was less prevalent in clinically indicated respiratory swabs in the probiotic cohort during the intervention (27% vs 56%; p=0.03), especially when commenced prior to 4 years old. Fecal M2-pyruvate kinase decreased in the probiotic cohort from baseline to 12 months. This study provides support for multi-strain probiotics in CwCF, even in the era of modulator therapy.

BACKGROUND:Ataxia-telangiectasia (A-T) is a rare multisystem disease characterised by neurodegenerative cerebellar ataxia, lung disease, immune deficiency, high cancer risk, and mitochondrial dysfunction. A-T cells demonstrate defective endoplasmic reticulum-mitochondrial connectivity disrupting calcium homoeostasis and mitochondrial fusion, which are corrected in vitro by the triheptanoin metabolite, heptanoate. METHODS:We performed a Phase 2a/b trial of triheptanoin with a three-arm placebo-controlled dose-escalation design. Doses escalated at 2-month intervals for 12 months in the sequence 0%, 10%, 20%, 35% of calculated caloric intake. The primary outcome was cell death in respiratory epithelial cells. Key secondary outcomes included scales for assessment and rating of ataxia (SARA), international cooperative ataxia rating scale (ICARS), speech and swallowing function, and novel biomarker discovery. FINDINGS:31 participants with A-T were enrolled aged from 4 to 37 years (median 16-years). For the maximum dose vs. placebo or no dose, significant improvements was observed for the primary outcome percent nasal cell death (mean difference (MD) = -9.7%, 95% confidence interval (CI) -16.0, 4.6). The SARA subscale kinetic function improved (MD = -5.8, 95% CI -10.4, -1.2), as did ICARS subscales gait (MD = -0.5, 95% CI -0.9, -0.1) and fine motor disturbance (MD = -2.7, 95% CI -4.3, -1.1). Speech intelligibility (MD = -12.8, 95% CI -21.2, -4.3) and swallowing safety (-0.9, 95% CI -1.6, -0.3) improved. Adverse events including abdominal pain, nausea, vomiting, and diarrhoea, requiring dose capping at 20%, were observed in 12 (38%) participants. INTERPRETATION:Improvements in mitochondrial function in A-T cells in vivo in patients occurred after triheptanoin. The biomarkers neurofilament light chain and interferon signature stimulated gene scores may allow for monitoring of disease progression and treatment response. FUNDING:Funded by Medical Researcher Futures Fund Australia (GA89314), The University of Queensland, Wesley Research Institute, and BrAshA-T.

INTRODUCTION:Mycobacteroides abscessus (MABS) is within the non-tuberculous mycobacteria family. It inhabits soil and water, exhibits multi-antibiotic resistance and causes opportunistic lung infections, which may progress to symptomatic MABS-pulmonary disease (MABS-PD) associated with substantial morbidity, increased healthcare utilisation, impaired quality of life and increased mortality. Treatment regimens for MABS-PD are highly variable, not evidence-based and involve complex, expensive drug combinations administered for prolonged periods (>12 months) with frequent adverse effects and treatment failure. There is an urgent need for safe, efficacious and cost-effective MABS-PD therapy. Here, we describe the Master Protocol for the Finding the Optimal Regimen for Mycobacteroides abscessus Treatment (FORMaT) trial. FORMaT aims to determine the most effective and best tolerated treatment for MABS-PD as defined by MABS clearance from respiratory samples with good treatment tolerance. METHODS AND ANALYSIS:FORMaT is an international multicentre, adaptive platform trial evaluating treatment combinations for MABS-PD. Participants are randomised multiple times during the trial, with assessment of the primary outcome of clearance of MABS infection with good treatment tolerance. Initially, therapies recommended in international consensus guidelines are being tested. Data obtained will eliminate therapies lacking efficacy or causing unacceptable toxicity. Novel treatments can then be added and tested against previously determined optimal approaches, leading in an iterative fashion to improved microbiological clearance and health outcomes. In parallel, an Observational cohort and several integrated and discovery studies are embedded in FORMaT to identify biomarkers of MABS-PD and MABS clearance, clinical and radiographic treatment response, drug pharmacokinetics and Mycobacteroides genomics and resistome. ETHICS AND DISSEMINATION:The FORMaT Master Protocol and related documents are approved by regulatory authorities in each participating jurisdiction and/or site. Results will be published in peer-reviewed journals and presented at scientific meetings. De-identified, aggregated data will be shared on an approved online platform. TRIAL REGISTRATION NUMBERS:NCT04310930, ANZCTR12618001831279, 2020-000050-10, ISRCTN67303903.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children 6 through 11 years of age with cystic fibrosis (CF) and at least one F508del allele in a 24-week phase 3 study. Children completing this study could enroll into a 192-week extension study. Evaluate long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years. In this 2-part (Part A [96-weeks] and Part B [96-weeks]) phase 3 extension study, children <12 years weighing <30 kg received ELX 100 mg once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and children weighing ≥ 30 kg or aged ≥12 years received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h. Sixty-four children (F/MF [n=36] and F/F [n=28]) received ≥ 1 dose of ELX/TEZ/IVA. Mean exposure was 156.2 weeks and 60.9% of children (n=39) completed treatment in both parts of this 192-week study. The primary endpoint was safety. All children had adverse events (AEs), which for most were mild (31.3%) or moderate (64.1%) and generally consistent with common manifestations of CF. Two children (3.1%) had non-serious AEs that lead to treatment discontinuation (increased alanine aminotransferase [n=1] and aggression [n=1]). Secondary endpoints focused on efficacy. From parent study baseline, improvements were seen in ppFEV1 (9.6 percentage points; 95% CI: 5.4, 13.7), sweat chloride concentration (-57.9 mmol/L; 95% CI: -63.3, -52.5), CFQ-R respiratory domain score (10.0 points; 95% CI: 6.9, 13.0), LCI2.5 (-2.33; 95% CI: -2.87, -1.79), and BMI z-score (0.39; 95% CI: 0.19, 0.59) at Week 192. Rate of pulmonary exacerbations per year was 0.05. The annualized rate of change in ppFEV1 and LCI2.5 was -0.09 percentage points (95% CI: -1.01, 0.84) and -0.07 units (95%CI: -0.12, -0.01), respectively. In this 4-year extension study in children ≥6 years, the longest clinical trial experience with a CFTR modulator in this pediatric population, ELX/TEZ/IVA remained generally safe and well-tolerated with no new safety findings. Clinically meaningful improvements in lung function, CFTR function, and nutritional status reported in the parent study were maintained. These results confirm the long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years. Clinical trial registration available at www. gov, ID: NCT04183790.

Rationale: Mycobacterium abscessus (MABS) group bacteria cause lethal infections in people with chronic lung diseases. Transmission mechanisms remain poorly understood; the detection of dominant circulating clones (DCCs) has suggested the potential for person-to-person transmission. Objectives: This study aimed to determine the role of drinking water in the transmission of MABS. Methods: A total of 289 isolates were cultured from respiratory samples (n = 231) and drinking water sources (n = 58) across Queensland, Australia. Measurements and Main Results: Whole-genome sequences were analyzed to identify DCCs and determine relatedness. Half of the isolates (n = 144; 49.8%) clustered with previously described DCCs, of which 30 formed a clade within DCC5. Pan-genomic analysis of the water-associated DCC5 clade revealed an enrichment of genes associated with copper resistance. Four instances of plausible epidemiological links were identified between genomically related clinical and water isolates. Conclusions: We provide evidence that drinking water is a reservoir for MABS and may be a vector in the chain of MABS infection.

BACKGROUND:Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in children aged 6-11 years with cystic fibrosis (CF) heterozygous for F508del and a minimal function CF transmembrane conductance regulator (CFTR) variant (F/MF genotypes) in a 24-week, placebo-controlled trial. We conducted a 96-week open-label extension study for children who completed the 24-week parent study. METHODS:In this phase 3b extension study, dosing was based on weight and age, with children weighing <30 kg and aged <12 years receiving ELX 100 mg once daily, TEZ 50 mg once daily and IVA 75 mg every 12 h, and children ≥30 kg or ≥12 years receiving ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h. The primary end-point was safety and tolerability. Secondary and other efficacy end-points included absolute changes from parent study baseline in sweat chloride concentration, lung clearance index (LCI2.5), percentage predicted forced expiratory volume in 1 s (FEV1) and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. RESULTS:A total of 120 children were enrolled and dosed. 118 children (98.3%) had adverse events (AEs), which for most were mild (43.3%) or moderate (48.3%) in severity. The most common AEs (≥20% of children) were COVID-19 (58.3%), cough (51.7%), nasopharyngitis (45.0%), pyrexia (40.0%), headache (37.5%), upper respiratory tract infection (30.8%), oropharyngeal pain (26.7%), rhinitis (24.2%), abdominal pain (22.5%) and vomiting (20.0%). Children who transitioned from the placebo and ELX/TEZ/IVA groups of the parent study had improvements from parent study baseline at Week 96 in mean sweat chloride concentration (-57.3 (95% CI -61.6- -52.9) and -57.5 (95% CI -62.0- -53.0) mmol·L-1), LCI2.5 (-1.74 (95% CI -2.09- -1.38) and -2.35 (95% CI -2.72- -1.97) units), FEV1 % pred (6.1 (95% CI 2.6-9.7) and 6.9 (95% CI 3.2-10.5) percentage points) and CFQ-R respiratory domain score (6.6 (95% CI 2.5-10.8) and 2.6 (95% CI -1.6-6.8) points). CONCLUSIONS:ELX/TEZ/IVA treatment was generally safe and well tolerated, with a safety profile consistent with the parent study and older age groups. After starting ELX/TEZ/IVA, children had robust improvements in sweat chloride concentration and lung function that were maintained through 96 weeks. These results demonstrate the safety and durable efficacy of ELX/TEZ/IVA in this paediatric population.

AIM:To report on the management of a toddler who had accidental ingestion of an unknown amount of paraquat, with treatment including continuous renal replacement therapy (CRRT), steroids and antifibrinolytics at a tertiary-level health system. METHODS:A 16-month-old child weighing 10 kg accidentally ingested an unknown amount of Gramoxone containing paraquat. The child was transferred to a tertiary centre Paediatric Intensive Care Unit (PICU) where she was electively intubated and commenced on CRRT at 7 hours and 15 minutes post-ingestion. She was also treated with activated charcoal, methylprednisolone, N-acetylcysteine infusion and pirfenidone. Paraquat blood and urine samples were monitored throughout her PICU admission. RESULTS:The child did not exhibit respiratory distress or significant hypoxia during the admission. She developed ulceration of the lips, mouth and tongue on day 2 which improved after 48 hours. Feed intolerance and pneumatosis intestinalis were managed conservatively. Interstitial changes were noted on chest x-ray on day 3 and pirfenidone was initiated to minimise the risk of pulmonary fibrosis. The child was discharged from PICU to the general ward for further observation. At follow-up, there has been no evidence of pulmonary fibrosis up to 6 months post-discharge. CONCLUSIONS:This case highlights the toxicity of Paraquat and importance of early management and urgent transfer of paraquat poisoning cases to specialised medical centres. Prompt interventions including activated charcoal, N-acetylcysteine, CRRT and pirfenidone can improve patient prognosis and reduce the risk of long-term complications such as pulmonary fibrosis in paediatric paraquat toxicity.

Background People with cystic fibrosis (CF) are recommended to wear face-masks when in healthcare settings. We previously demonstrated that face-masks significantly reduce the release of Pseudomonas aeruginosa (P. aeruginosa) aerosols during coughing in adults with CF. There is a knowledge gap in relation to the impact of mask wear in children with CF. This study aimed to examine the tolerability and effectiveness in lowering emissions of hospital-grade surgical and one type of commercially available cotton face-mask in children with CF. Methods Twenty children with CF and P. aeruginosa infection were recruited. Participants performed three cough manoeuvres in a validated cough aerosol system both with and without face-masks of differing wear time. Cough aerosols were sampled at two meters using an Andersen Cascade Impactor. Quantitative sputum and aerosol bacterial cultures were performed. Participants also rated the comfort levels of the face-masks. Results P. aeruginosa was cultured from the sputum in eight participants (40 %). During uncovered coughing (reference manoeuvre), seven of the 20 participants produced aerosols containing bacterial pathogens. There was a reduction in aerosolised bacterial load during coughing with both surgical and cotton face-masks. The mean percent reduction in CFU with both types of face-masks was 82 % (95 % CI 56 - 108) during the immediate face-mask wear test compared to the uncovered cough test. Face-masks were generally well tolerated. Conclusions Face-masks are well tolerated and effective in reducing cough-generated bacterial aerosols in children with CF.

Rationale: Elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) was shown to be safe and efficacious in children 6 through 11 years of age with cystic fibrosis (CF) and at least one F508del allele in a 24-week phase 3 study. Children completing this study could enroll into a 192-week extension study. Objectives: To evaluate the long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years of age. Methods: In this two-part (part A [96 wk] and part B [96 wk]) phase 3 extension study, children <12 years of age weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, and children weighing ≥30 kg or aged ≥12 years received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours. Measurements and Main Results: Sixty-four children (F508del/minimal function [n = 36] and F508del/F508del [n = 28]) received at least one dose of ELX/TEZ/IVA. Mean exposure was 156.2 weeks, and 60.9% of children (n = 39) completed treatment in both parts of this 192-week study. The primary endpoint was safety. All children had adverse events, which for most were mild (31.3%) or moderate (64.1%) and generally consistent with common manifestations of CF. Two children (3.1%) had nonserious adverse events that led to treatment discontinuation (increased alanine aminotransferase [n = 1] and aggression [n = 1]). Secondary endpoints focused on efficacy. From parent study baseline, improvements were seen in percentage predicted FEV1 (9.6 percentage points [95% confidence interval (CI), 5.4 to 13.7 percentage points]), sweat chloride concentration (-57.9 mmol/L [95% CI, -63.3 to -52.5 mmol/L]), Cystic Fibrosis Questionnaire-Revised respiratory domain score (10.0 points [95% CI, 6.9 to 13.0 points]), lung clearance index at a 2.5% stopping point (-2.33 [95% CI, -2.87 to -1.79]), and body mass index z-score (0.39 [95% CI, 0.19 to 0.59]) at Week 192. The rate of pulmonary exacerbations per year was 0.05. The annualized rates of change in percentage predicted FEV1 and lung clearance index at a 2.5% stopping point were -0.09 percentage points (95% CI, -1.01 to 0.84 percentage points) and -0.07 units (95% CI, -0.12 to -0.01 units), respectively. Conclusions: In this 4-year extension study in children ≥6 years of age, the longest clinical trial experience with a CFTR (cystic fibrosis transmembrane conductance regulator) modulator in this pediatric population, ELX/TEZ/IVA remained generally safe and well tolerated, with no new safety findings. Clinically meaningful improvements in lung function, CFTR function, and nutritional status reported in the parent study were maintained. These results confirm the long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years of age.Clinical trial registered with www.clinicaltrials.gov (NCT04183790).