Paul McNally

Introduction: The current cystic fibrosis (CF) care era, while hugely welcome, raises new challenges, particularly the need for more sensitive pulmonary outcome measures. Seeking further optimisation, we previously developed a Short extension to multiple breath washout measure (MBW _ShX ) which captures previously overlooked, under-ventilated lung units but lacks regional information. Functional lung MRI addresses this limitation. We hypothesised these measures would be more sensitive to change in tracking CF lung disease than usual clinical respiratory function tests. Methods: Forty-six people with (pw)CF, median age 15 (range 6–55) years were recruited to a single-centre study. While clinically stable, pwCF performed OE-MRI, MBW+/- _ShX and spirometry at baseline and at 6 monthly intervals over 18 months of follow-up. A subgroup of pwCF (n=20) and age-matched healthy controls (HC, n=20) performed two repeatability visits within 6 weeks. Results: OE-MRI/MBW _ShX were well tolerated, differentiated HC and CF groups, and were repeatable with negligible differences between two visits ShX parameters worsened at 12 months (p1 + LCI _2.5 ) did not change significantly. Conclusions: OE-MRI/MBW _ShX are novel, sensitive tools to track progression of abnormalities in lung structure/function. Such progression may not be detected by conventional outcome measures. CF transmembrane conductance regulator (CFTR) modulators have been transformative for many pwCF and generally lead to substantial improvements in lung health. Stable FEV ₁ over longer time periods and, during mucoactive treatment withdrawal, may give false reassurance. OE-MRI/MBW _ShX reveal the likely less welcome reality that lung-disease progresses despite CFTR modulators. These measures could be considered in future studies when enhanced sensitivity is required.

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 (NCT 04183790).

ENHANCE is a multicentre, longitudinal study examining the natural history of early cystic fibrosis (CF) disease manifestations in children. We hypothesise that the prevalence, presentation and natural history of disease manifestations of CF in young children will change significantly in the next decade with advances in the understanding and treatment of CF, including the use of therapies aimed at improving CFTR function. The study has been co-developed with the CF community, in order to try to answer questions of key importance to people with CF and their caregivers. The study will longitudinally monitor lung health using nitrogen multiple breath washout testing and spirometry, lung structure using spirometry-controlled computed tomography scanning, gastrointestinal health using gut microbiome, gut inflammation and abdominal symptom scores, pancreatic function using faecal elastase, liver function using liver blood tests and liver ultrasound, and sweat chloride. Mental health will be longitudinally assessed using questionnaires for mood (PROMIS, GAD-7), quality of life (CFQ-R) and psychosocial functioning (Pediatric Symptom Checklist). There are three cohorts in the study: infants with CF diagnosed by newborn screening (n=250), children aged 0–6 years and currently attending CF centres (n=200) and healthy newborn infant controls (100). The study will be conducted over 5 years in the first phase with a plan to extend through further phases in the future. We envisage that the study will provide important evidence to enable healthcare staff and families to guide the care of children with CF in the future.

Rationale: Clinical trials have shown that use of elexacaftor/tezacaftor/ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition, and quality of life in people with cystic fibrosis (CF). Little is known about the impact of ETI on ventilation inhomogeneity and lung structure. Objectives: RECOVER is a real-world study designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (lung clearance index; LCI2.5) and FEV1. Secondary endpoints included spirometry-controlled chest computed tomography (CT) scores. Methods: The study was conducted in seven sites in Ireland and the United Kingdom. Participants ages 12 years and older who were homozygous for the F508del mutation (F508del/F508del) or heterozygous for F508del and a minimum-function mutation (F508del/MF) were recruited before starting ETI and were followed up over 12 months. LCI2.5 was measured using nitrogen multiple breath washout (MBW) at baseline and at 6 and 12 months. Spirometry was performed as per the criteria of the American Thoracic Society and the European Respiratory Society. Spirometry-controlled chest CT scans were performed at baseline and at 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life Questionnaire—Revised (CFQ-R), and sweat chloride. Measurements and Main Results: One hundred seventeen people with CF ages 12 and older were recruited to the study. Significant improvements were seen in LCI scores (−2.5; 95% confidence interval [CI], −3.0, −2.0) and in the percents predicted for FEV1 (8.9; 95% CI, 7.0, 10.9), FVC (6.6; 95% CI, 4.9, 8.3), and forced expiratory flow between 25% and 75% of expired volume (12.4; 95% CI, 7.8, 17.0). Overall PRAGMA-CF scores reflecting airway disease improved significantly (−3.46; 95% CI, −5.23, −1.69). Scores for trapped air, mucus plugging, and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (−43.1; 95% CI, −47.4, −38.9) and F508del/MF (−42.8; 95% CI, −48.5, −37.2) groups. Scores on the Respiratory Domain of the CFQ-R improved by 14.2 points (95% CI, 11.3, 17.2). At 1 year, sweat chloride levels were significantly lower for the F508del/F508del group compared with scores for the F508del/MF group (33.93 vs. 53.36, P < 0.001). Conclusions: ETI is associated with substantial improvements in LCI2.5, spirometry, and PRAGMA-CF CT scores in people with CF ages 12 years and older. ETI led to improved nutrition and quality of life. People in the F508del/F508del group had significantly lower sweat chloride on ETI treatment compared with the F508del/MF group. Clinical trial registered with www.clinicaltrials.gov (NCT 04602468).