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).

BACKGROUND:Cystic fibrosis (CF) is a chronic genetic disorder requiring regimented visits for maintenance of care. The COVID-19 pandemic accelerated the accessibility of telehealth (TH) and forced a trial of incorporating remote care into routine CF care. The CF Learning Network (CFLN) organized for data sharing into a telehealth innovation lab (TH-iLab) to improve access to the interdisciplinary care team and co-produced shared agenda-setting. METHODS:All persons with CF (PwCF) with a CF diagnosis in the CF Foundation Registry (CFFPR) from 1/2020-12/2021 were included and categorized into CFLN TH-iLab, CFLN TH-iLab non-participants, and non-CFLN programs. HYPOTHESIS:standardized TH implementation in the CFLN TH-iLab is associated with increased access to the CF care model and results in similar lung function and nutrition health outcomes. RESULTS:In 2020 and 2021, the average number of TH visits per person per year and the percentage of PwCF with one or more TH visits per year were higher in the CFLN TH-iLab than in the other groups. Lung function was highest in PwCF, followed by a program that was part of the CFLN TH-iLab in 2020 and 2021. Anthropometric measurements, spirometry, and attainment of microbiology cultures were similar among all three groups. Access to interdisciplinary care was highest in the CFLN non-TH-iLab group. CONCLUSION:Integrating TH into CF care in the CFLN TH-iLab provided access to care during the COVID-19 pandemic without compromising clinical outcomes. Further research on optimizing the telehealth experience for PwCF can help better understand TH's long-term impact on CF care.

Background: Social determinants of health (SDOH) and health-related social needs (HRSN) drive disparities in lung function, nutrition, and survival in People with Cystic Fibrosis (PwCF). Addressing HRSN can improve access to care, yet standardized screening and intervention methods remain underutilized. Objectives: The aim of this project was to develop, test, and refine a remote HRSN screening and intervention model across multiple cystic fibrosis (CF) centers. Design: A multicenter, prospective Quality Improvement (QI) initiative Methods: Four CF centers, serving both pediatric and adult populations, piloted an electronic HRSN screening tool and a remote social need intervention strategy. Developed collaboratively with CF clinicians and patient and family partners (PFPs), the tool assesses nine HRSN domains. Multidisciplinary teams, including PwCF, held regular meetings to tailor implementation to each site’s existing clinical workflow and staff structure. Over 1 year, each site conducted iterative Plan-Do-Study-Act (PDSA) cycles every 2 weeks to refine the screening process, sharing adaptations across centers. Results: All four CF centers successfully implemented the remote HRSN screening and intervention workflows, completing 26 iterative PDSA cycles to refine site-specific processes. Study site meetings were held with multidisciplinary attendance at 100% of meetings. The screening tool was integrated into pre-visit planning and telehealth workflows, allowing for social worker follow-up of identified needs. Multidisciplinary collaboration from all sites resulted in the generation of a comprehensive library of local and regional resources to support unmet needs identified during screening. Narrative patient testimonial highlighted the screening tool’s effectiveness in facilitating discussions about social needs and connecting individuals to available resources from the perspective of PwCF. Conclusion: Our study has shown that HRSN screening and intervention are feasible, adaptable and acceptable to PwCF. Next steps include gathering comprehensive data on screening and intervention rates, domains of unmet social needs across regions, and sustainability interventions. Expanding HRSN screening and intervention to other CF Centers can provide data to support public policy and advocacy initiatives for reducing health disparities driven by SDOH.

Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles. Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged >= 6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing,30 kg received ELX 100mg once daily/TEZ 50mg once daily/IVA 75mg every 12 hours, whereas children weighing >= 30 kg received ELX 200mg once daily/TEZ 100mg once daily/IVA 150mg every 12 hours (adult dose). The 96-week analysis of part A of this extension study is reported here. Measurements and Main Results: Sixty-four children (F/MF genotypes, n = 36; F/F genotype, n = 28) were enrolled and received one or more doses of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of CF disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. Fromparent study baseline atWeek 96 of this extension study, the mean percent predicted FEV1 increased (11.2 [95% confidence interval (CI), 8.3 to 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI, -65.9 to -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI, 11.4 to 15.1] points), and lung clearance index 2.5 decreased (-2.00 [95% CI, -2.45 to -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in percent predicted FEV1 was 0.51 (95% CI, -0.73 to 1.75) percentage points per year. Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged >= 6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population.

Introduction: A learning health network is a type of learning health system in which stakeholders use network organization to improve health and health care. Building on existing resources in the cystic fibrosis (CF) community, the Cystic Fibrosis Learning Network (CFLN) was designed to improve medical outcomes and quality of life through an intentional focus on achieving reliable evidence-based chronic care delivery and creating a system for data-driven collaborative learning. Methods: We describe the development and growth of the CFLN considering six domains of a Network Maturity Grid: system leadership; governance and policy management; quality improvement (QI); engagement and community building; data and analytics; and research. We illustrate the impact of the CFLN experience on chronic care processes and indicators of collaborative infrastructure. Results: The CFLN represents 36 accredited care centers in the CF Foundation Care Center Network caring for over 6300 patients. Of 6779 patient clinical care visits/quarter, 77% are entered into the CF Foundation Patient Registry within 30 days, providing timely means to track outcomes. Collaborative visit planning is occurring in 93% of clinical care visits to share agenda setting with patients and families. Almost all CFLN teams (94%, n = 34) have a patient/family partner (PFP), and 74% of PFPs indicate they are actively participating, taking ownership of, or leading QI initiatives with the interdisciplinary care team. In 2022, 97% of centers reported completing 1-13 improvement cycles per month, and 82% contributed to monthly QI progress reports to share learning. Conclusion: The CFLN is a maturing, collaborative infrastructure. CFLN centers practice at an advanced level of coproduction. The CFLN fosters interdisciplinary and PFP leadership and the performance of consistent data-driven improvement cycles. CFLN centers are positioned to respond to rapid changes in evidence-based care and advance the practice of QI and implementation science on a broader scale.

Cystic fibrosis (CF) lung disease starts early in life and progresses throughout infancy and the preschool years (1, 2). Therapeutic strategies initiated early in life have the potential to reverse this process and maintain lung health. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that increases the channel’s opening probability. Remarkable and sustained lung function improvements have been demonstrated in patients aged 6 years and older with gating CFTR mutations such as G551D on at least one allele (3, 4). A recent open-label trial provided evidence for safety and nutritional benefits in children aged 2–5 years, but lung function was not systematically assessed within this study (5). The lung clearance index (LCI) measured by multiple-breath washout has been shown to be a sensitive measure to capture lung function abnormalities in patients with CF and is feasible for use in preschool children because it requires minimal cooperation. LCI can also be used to detect treatment effects in interventional trials (6, 7). As part of GOAL (G551D Observational Study) (NCT 01521338), a multicenter longitudinal observational study to explore biomarkers as well as clinical and physiological characteristics of patients with CF with gating mutations initiated on ivacaftor therapy (8), we report the results of LCI in preschool patients assessed before and after ivacaftor treatment initiation. Multiple-breath washout measurements based on nitrogen as the tracer gas using the EXHALYZER D (Eco Medics) were performed in preschool children with CF aged 3 to 5 years. Measurements were performed in accordance with recently published standards for preschool children (9) and modifications of the equipment to reduce dead space as described previously (2). Baseline was defined as the predose measurement immediately preceding the start of treatment; all other medications were kept constant throughout the study period. Changes in LCI from baseline to 1 month and from baseline to 6 months after the start of ivacaftor treatment were analyzed using nonparametric Wilcoxon signed-rank tests. Relative changes in LCI compared with baseline were evaluated using one-sample Kolmogorov-Smirnov tests. This analysis includes five subjects with CF enrolled in the GOAL study in the United States and an additional four preschoolaged patients with CF started on ivacaftor at the Hospital for Sick Children in Toronto (SickKids). Baseline characteristics of the study population are displayed in Table 1. Median sweat chloride concentration at baseline was 103 mEq/L. All nine patients carried one copy of the G551D mutation, with seven patients being compound heterozygous for F508del. The average LCI at baseline was 10.6 (interquartile range [IQR], 8.9 to 11.2); seven of nine patients had LCI values above the upper limit of normal, reflecting increased ventilation inhomogeneity (2) (Figure 1A). Mean sweat chloride concentrations decreased to 46 mEq/L 1 month after ivacaftor initiation (mean change [IQR],256 [261 to 247]). Within-patient LCI significantly improved 1 month after the first dose of ivacaftor (median LCI at 1 mo, 7.10 [6.6 to 8.5]; P = 0.02). The improvement in LCI was maintained 6 months after the first dose (median LCI, 7.3 [7.3 to 7.6]; P = 0.03). Assessing relative changes in LCI at 1 month and 6 months after ivacaftor treatment yielded similar results. LCI significantly improved from baseline at both 1 month (median change in LCI from baseline, 223.6% [IQR, 234.2 to 220.2]; P, 0.001) and 6 months post-treatment (median change in LCI from baseline, 224.6% [IQR, 231.4 to 220.4]; P, 0.001). Thus, rapid and sustained improvements in LCI were demonstrated with ivacaftor therapy that exceeded the between-test reproducibility and thus the physiologically relevant change for quarterly LCI measurements in health, which we recently demonstrated to be 15% in preschool children (10). The only two patients not showing an improvement in LCI had normal baseline values of LCI. The observed effect size was similar to what has been described in older patients with CF treated with ivacaftor (6, 11). This study also supports the concept that LCI is a suitable outcome measure to capture changes in lung function in preschool children on CFTR modulator therapy, and also that ivacaftor helps improve early airway disease even in young children. n

Introduction: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare pulmonary disorders. Our objectives are to advance knowledge on clinical features, management, and outcomes of this population. Methods: The Children’s Interstitial and Diffuse Lung Disease Research Network (ChILDRN) established a longitudinal observational study in 2016 using a national platform for single IRB reliance agreements with 13 participating sites across the United States. Results: 254 subjects have been enrolled to date. Specific chILD diagnoses and clinical characteristics are summarized in Table 1. Overall mean age at study enrollment was 101±73 months. Identified morbidity included home oxygen supplementation in 71% at any time and 44% with ongoing requirement. Failure to thrive was noted in 53%. 46% of subjects had undergone lung biopsy; genetic studies were used in diagnosis for 23%. Pulmonary function abnormalities varied based on disease subgroup. Conclusions: The first multicenter prospective study of chILD in the U.S. indicates substantial morbidity with variable phenotypes in different forms of chILD. This cohort provides a framework for future longitudinal studies focused on elucidation of the genetic and molecular underpinnings of these disorders, development of targeted therapies, and optimization of supportive care.