Virtual Physical Prehabilitation in Lung Transplant Candidates: A Proof-of-Concept Study.

This study aimed to preliminary test the effectiveness of 12-week virtual physical prehabilitation program followed by a maintenance phase. The main objective was to estimate the extent to which it affects exercise capacity, frailty, lower limb strength and health-related quality of life (HRQOL) in lung transplant candidates. The program offered supervised strengthening exercises, independent aerobic exercises and weekly phone calls (maintenance phase). Primary outcome was the six-minute walk distance (6MWD). Secondary outcomes: the Short Physical Performance Battery (SPPB), five-times sit-to-stand test (5STS), the St George's Respiratory Questionnaire (SGRQ) for HRQOL. Twenty patients were included (mean age 57.9; 6 women/14 men); fourteen completed the prehabilitation program and 5 completed the maintenance phase. There was no statistically significant improvement in 6MWD, SPPB or SGRQ after the 12-week program. Most patients either maintained or improved the 6MWT and SPPB scores. There was a significant improvement in the 5STS. After the maintenance phase, most patients either improved or maintained their scores in all outcomes except for the sub-score of symptoms in the SGRQ. A 12-week virtual physical prehabilitation program with a 12-week maintenance phase can help lung transplant candidates improve or maintain their physical function while waiting for transplantation.

Reduced exercise capacity for muscle mass in adolescents living with obesity.

BACKGROUND: Adolescents living with obesity (AlwO) can have limited exercise capacity. Exercise capacity can be predicted by a 2-factor model comprising lung function and leg muscle function, but no study has looked at cycling leg muscle function and its contribution to cycling exercise capacity in AlwO. METHODS: Twenty-two nonobese adolescents and 22 AlwO (BMI > 95 percentile) were studied. Anthropometry, body composition (dual-energy X-ray absorptiometry), spirometry, 30-s isokinetic work capacity, and maximal exercise (cycle ergometry) were measured. RESULTS: AlwO had greater total body mass, lean body mass, and lean leg mass (LLM). Lung function trended higher in AlwO. Leg 30-s work did not differ in absolute terms or per allometrically scaled LLM. Peak oxygen consumption did not differ between the groups in absolute terms or as percent predicted values (79.59 ± 14.6 vs. 82.3 ± 11.2% predicted control versus ALwO) but was lower in AlwO when expressed per kg body mass, kg lean body mass, scaled lean body mass, and LLM. Peak oxygen consumption related to both lung function and 30-s work, with no observed group effect. 30-s leg work related to the scaled LLM, with a small group effect. There was some correlation between leg work and time spent in moderate to vigorous physical activity in AlwO (rs = 0.39, p = .07). CONCLUSION: AlwO have larger LLM and preserved exercise capacity, when expressed as percentage of predicted, but not per allometrically scaled LLM. Increasing time spent in moderate to vigorous activity may benefit AlwO.

Preventative therapies for respiratory Syncytial virus (RSV) in children: Where are we now?

Respiratory Syncytial Virus (RSV) is a leading cause of hospitalization in young children and represents a substantial health-care burden around the world. Advances in research have helped identify the prefusion F protein as the key target component in RSV immunization. In this article, we review the previous, current, and ongoing research efforts for immunization against RSV in children. We present the different types of immunization which include monoclonal antibodies, maternal immunization and vaccines while addressing the challenges of preventing RSV infections in the pediatric population.

Canadian Cystic Fibrosis-related Diabetes Clinical Practice Survey: Analysis of Current Practices and Gaps in Clinical Care.

OBJECTIVES: Our aim in this study was to identify challenges and gaps in Canadian practices in screening, diagnosis, and treatment of cystic fibrosis-related diabetes (CFRD), with the goal of informing a Canadian-specific guideline for CFRD. METHODS: We conducted an online survey of health-care professionals (97 physicians and 44 allied health professionals) who care for people living with CF (pwCF) and/or CFRD (pwCFRD). RESULTS: Most pediatric centres followed <10 pwCFRD and adult centres followed >10 pwCFRD. Children with CFRD are usually followed at a separate diabetes clinic, whereas adults with CFRD may be followed by respirologists, nurse practitioners, or endocrinologists in a CF clinic or in a separate diabetes clinic. Less than 25% of pwCF had access to an endocrinologist with a special interest or expertise in CFRD. Many centres perform screening oral glucose tolerance testing with fasting and 2-hour time points. Respondents, especially those working with adults, also indicate use of additional tests for screening not currently recommended in CFRD guidelines. Pediatric practitioners tend to only use insulin to manage CFRD, whereas adult practitioners are more likely to use repaglinide as an alternative to insulin. CONCLUSIONS: Access to specialized CFRD care may be a challenge for pwCFRD in Canada. There appears to be wide heterogeneity of CFRD care organization, screening, and treatment among health-care providers caring for pwCF and/or pwCFRD across Canada. Practitioners working with adult pwCF are less likely to adhere to current clinical practice guidelines than practitioners working with children.

Post-transplant outcomes among cystic fibrosis patients undergoing lung transplantation colonized by Burkholderia: A single center cohort study.

BACKGROUND: Prior infection with Burkholderia cepacia complex (BCC) has been associated with poorer outcomes after lung transplantation, posing an important dilemma for cystic fibrosis (CF). Although current guidelines consider BCC infection to be a relative contraindication, some centers continue to offer lung transplantation to BCC-infected CF patients. METHODS: We conducted a retrospective cohort study which included all consecutive CF-LTR between 2000 and 2019 to compare the postoperative survival of BCC-infected CF lung transplant recipients (CF-LTR) to BCC-uninfected patients. We used a Kaplan-Meier analysis to compare survival of BCC-infected to BCC-uninfected CF-LTR and fitted a multivariable Cox model, adjusted for age, sex, BMI and year of transplantation as potential confounders. As an exploratory analysis, Kaplan-Meier curves were also stratified by the presence of BCC and urgency of transplantation. RESULTS: A total of 205 patients were included with a mean age of 30.5 years. Seventeen patients (8%) were infected with BCC prior to LT. Patients were infected with the following species: B. multivorans5, B. vietnamiensis3, combined B. multivorans and B. vietnamiensis3 and others4. None of the patients were infected with B. cenocepacia. Three patients were infected with B. gladioli. One-year survival was 91.7% (188/205) for the entire cohort, 82.4% (14/17) among BCC-infected CF-LTR, and 92.5% (173/188) among BCC uninfected CF-LTR (crude HR = 2.19; 95%CI 0.99-4.85; p = 0.05). In the multivariable model, presence of BCC was not significantly associated with worse survival (adjusted HR 1.89; 95%CI 0.85-4.24; p = 0.12). In the stratified analysis for both presence of BCC and urgency of transplantation, urgency of transplantation among BCC-infected CF-LTR appeared to be associated with poorer outcome (p = 0.003 across the 4 subgroups). CONCLUSION: Our results suggest that non-cenocepacia BCC-infected CF-LTR have comparable survival rate to BCC-uninfected CF-LTR.

Cystic fibrosis related diabetes is not associated with maximal aerobic exercise capacity in cystic fibrosis: a cross-sectional analysis of an international multicenter trial.

BACKGROUND: Previous studies have reported differences in aerobic exercise capacity, expressed as peak oxygen uptake (VO2peak), between people with and without cystic fibrosis (CF) related diabetes (CFRD). However, none of the studies controlled for the potential influence of physical activity on VO2peak. We investigated associations between CFRD and VO2peak following rigorous control for confounders including objectively measured physical activity. METHODS: Baseline data from the international multicenter trial ACTIVATE-CF with participants ≥12 years performing up to 4 h per week of vigorous physical activity were used for this project. Multivariable models were computed to study associations between CFRD and VO2peak (mL.min-1) adjusting for a set of pre-defined covariates: age, sex, weight, forced expiratory volume in 1 s (FEV1), breathing reserve index, Pseudomonas aeruginosa infection, and physical activity (aerobic step counts from pedometry). Variables were selected based on their potential confounding effect on the association between VO2peak and CFRD. RESULTS: Among 117 randomized individuals, 103 (52% female) had a maximal exercise test and were included in the analysis. Participants with (n = 19) and without (n = 84) CFRD did not differ in FEV1, physical activity, nutritional status, and other clinical characteristics. There were also no differences in VO2peak (mL.min-1 or mL.kg-1.min-1 or% predicted). In the final multivariable model, all pre-defined covariates were significant predictors of VO2peak (mL.min-1), however CFRD [coefficient 82.1, 95% CI -69.5 to 233.8, p = 0.28] was not. CONCLUSIONS: This study suggests no meaningful differences in VO2peak between people with and without CFRD given comparable levels of physical activity.

Lung ultrasound findings in asymptomatic healthy children with asthma.

BACKGROUND: Lung ultrasound (LUS) has been shown to be an effective tool to rapidly diagnose certain causes of pediatric respiratory distress. However, very little is known about LUS findings in pediatric asthma. OBJECTIVES: The primary objective of this study was to characterize LUS findings in a cohort of pediatric patients with a definitive diagnosis of asthma, outside of an asthma exacerbation. METHODS: Eligible patients, aged 6-17 years old and diagnosed with asthma, underwent LUS during an outpatient visit. LUS was conducted using a six-zone scanning protocol. Presence of a LUS artifact was defined by one or more of the following: ≥3 B-lines per intercostal space, pulmonary consolidation, and/or pleural abnormality. Images were interpreted by an expert sonographer blinded to patient clinical characteristics. RESULTS: Fifty-two patients were included. 10/52 (19.2%) patients demonstrated the presence of LUS artifacts: 8 with ≥3 B-lines, 1 with consolidation >1 cm, and 7 with subpleural consolidations <1 cm, 1 with a pleural line abnormality. Artifacts were seen in the right anterior and lateral zones in 60% of participants and were limited to 1-2 intercostal space(s) within one lung zone in all participants. No association was found between presence of LUS artifacts and asthma control or severity. CONCLUSION: To our knowledge, this is the first report of LUS findings in outpatient pediatric asthma. LUS artifacts in asthmatic children can be seen outside of acute exacerbations. Such baseline findings need to be taken into consideration when using LUS for the acute evaluation of a pediatric patient with asthma.

New-onset Obesity After Lung Transplantation: Incidence, Risk Factors, and Clinical Outcomes.

BACKGROUND: Lung transplant (LTx) recipients who gain weight after transplantation may experience an upward shift in body mass index (BMI) that places them in the obese category. The incidence, risk factors, and impact on metabolic health and mortality of new-onset obesity have not been documented in the LTx setting. METHODS: This single-center retrospective study included 564 LTx recipients. Individuals were stratified according to their BMI trajectories from pretransplant evaluation up to 10 y posttransplant. New-onset obesity was defined as a pretransplant BMI <30 kg/m 2 and posttransplant BMI >30 kg/m 2 . The incidence, risk factors, and posttransplant diabetes mellitus, metabolic syndrome, and mortality of recipients with new-onset obesity were compared with those of nonobese (BMI <30 kg/m 2 , pre/post-LTx), consistently obese (BMI >30 kg/m 2 , pre/post-LTx), and obese recipients with weight loss (BMI >30 kg/m 2 pre-LTx, BMI <30 kg/m 2 post-LTx). RESULTS: We found that 14% of recipients developed obesity after transplantation. Overweight individuals (odds ratio [OR]: 9.01; 95% confidence interval [CI] [4.86-16.69]; P < 0.001) and candidates with chronic obstructive pulmonary disease (OR: 6.93; 95% CI [2.30-20.85]; P = 0.001) and other diagnoses (OR: 4.28; 95% CI [1.22-14.98]; P = 0.023) were at greater risk. Multivariable regression analysis showed that new-onset obesity was associated with a greater risk of metabolic syndrome (hazard ratio: 1.70; 95% CI [1.17-2.46]; P = 0.005), but not of posttransplant diabetes mellitus, than nonobesity. Recipients with new-onset obesity had a survival comparable to that of consistently obese individuals. CONCLUSIONS: A greater understanding of the multifaceted nature of post-LTx obesity may lead to interventions that are better tailored to the characteristics of these individuals.

Re-opening the pediatric pulmonary function laboratory during the ongoing COVID-19 pandemic.

The COVID-19 pandemic continues with new waves of intensification. This review provides an update based on international recommendations concerning the conduct of pulmonary function testing in a manner to limit risk to both patient and tester.

Characterizing pediatric lung ultrasound findings during a chemically induced bronchospasm.

BACKGROUND: Lung ultrasound (LUS) has been shown to be a useful clinical tool in pediatrics, but very little is known about the LUS findings of asthma in children. OBJECTIVES: The primary objective was to characterize LUS findings of pediatric patients before and after a chemically induced bronchospasm. The secondary objective was to evaluate the effect of bronchodilators on LUS findings. METHODS: Eligible children 6-17 years old presenting for a methacholine challenge test (MCT) in a pediatric respiratory clinic were recruited. Patients with viral symptoms were excluded. A six-zone LUS protocol was performed before and after the MCT, and after bronchodilator administration; video recordings were analysed by an expert blinded to the patient characteristics and MCT results. RESULTS: Forty-four patients were included in the study. Five patients had positive LUS findings at baseline. Nine patients out of 29 (31%) had new-onset positive LUS following a reactive MCT. There was a significant association between having a chemically induced bronchospasm and a positive LUS post-MCT (odds ratio [95% confidence interval]: 5.3 [1.0-27.7]; p = 0.05). Among patients who developed positive LUS findings post-MCT, four out of nine returned to having a negative LUS postbronchodilator administration. CONCLUSIONS: This is the first known report of an association between LUS findings and bronchospasm in pediatric patients. It is also the first documentation of resolution of LUS findings postbronchodilator administration. Most LUS findings observed were small and limited to a few intercostal spaces. Further research is required to quantify these findings and evaluate the effect of salbutamol on LUS.

A scoping review of mHealth monitoring of pediatric bronchial asthma before and during COVID-19 pandemic.

Mobile (m) Health technology is well-suited for Remote Patient Monitoring (RPM) in a patient's habitual environment. In recent years there have been fast-paced developments in mHealth-enabled pediatric RPM, especially during the COVID-19 pandemic, necessitating evidence synthesis. To this end, we conducted a scoping review of clinical trials that had utilized mHealth-enabled RPM of pediatric asthma. MEDLINE, Embase and Web of Science were searched from September 1, 2016 through August 31, 2021. Our scoping review identified 25 publications that utilized synchronous and asynchronous mHealth-enabled RPM in pediatric asthma, either involving mobile applications or via individual devices. The last three years has seen the development of evidence-based, multidisciplinary, and participatory mHealth interventions. The quality of the studies has been improving, such that 40% of included study reports were randomized controlled trials. In conclusion, there exists high-quality evidence on mHealth-enabled RPM in pediatric asthma, warranting future systematic reviews and/or meta-analyses of the benefits of such RPM.

Effects of a Partially Supervised Conditioning Program in Cystic Fibrosis: An International Multicenter, Randomized Controlled Trial (ACTIVATE-CF).

Rationale: The long-term effects of vigorous physical activity (PA) on lung function in cystic fibrosis are unclear. Objectives: To evaluate effects of a 12-month partially supervised PA intervention using motivational feedback. Methods: In a parallel-arm multicenter randomized controlled trial (ACTIVATE-CF), relatively inactive patients aged at least 12 years were randomly assigned (1:1 ratio) to an intervention group or control group. The intervention group consented to add 3 hours of vigorous PA per week, whereas the control group was asked not to change their PA behavior. Primary endpoint was change in percent predicted FEV1 (ΔFEV1) at 6 months. Secondary endpoints included PA, exercise capacity, exercise motives, time to first exacerbation and exacerbation rates, quality of life, anxiety, depression, stress, and blood glucose control. Data were analyzed using mixed linear models. Measurements and Main Results: A total of 117 patients (40% of target sample size) were randomized to an intervention (n = 60) or control group (n = 57). After 6 months, ΔFEV1 was significantly higher in the control group compared with the intervention group (2.70% predicted [95% confidence interval, 0.13-5.26]; P = 0.04). The intervention group reported increased vigorous PA compared with the control group at each study visit, had higher exercise capacity at 6 and 12 months, and higher PA at 12 months. No effects were seen in other secondary outcomes. Conclusions: ACTIVATE-CF increased vigorous PA and exercise capacity, with effects carried over for the subsequent 6 months, but resulted in better FEV1 in the control group.

Long-term bone mineral density changes and fractures in lung transplant recipients with cystic fibrosis.

BACKGROUND: Little is known about long-term bone mineral density (BMD) changes and fractures in lung transplant recipients with cystic fibrosis (CF). We examined femur and lumbar spine (LS) BMD changes in men and women with CF up to 10 years post-transplant and documented post-transplant fracture prevalence. METHODS: Retrospective study of individuals who had undergone a lung transplant (2000-2015) and had a pre-transplant and at least one BMD measurement after transplant. Vertebral fractures were assessed on chest computed tomography scans and other fractures abstracted from medical records. RESULTS: The cohort consisted of 131 individuals; 53% males, median age: 28 years [interquartile range: 24-35] and 31% having pre-transplant low bone mass. Most recipients were given bisphosphonates after transplant with proportion reaching 94% at 10 years. Up to 10 years post-transplant, men experienced positive or little change in LS BMD, indicating minimal loss from pre-transplant values. In contrast, women displayed negative changes in BMD up to 5 years post-transplant before recovering pre-transplant BMD values by 10 years. Similar patterns were observed at the femur BMD where men demonstrated a lower bone loss and faster recovery towards pre-transplant values than women. After transplant, 88% of recipients maintained their pre-transplant bone status, 3% experienced an improvement, mostly progressing from low bone mass to normal status whereas 9% had a deterioration of their pre-transplant bone status. Twenty-seven recipients suffered fractures in the post-transplant period. CONCLUSIONS: These findings underline that lung recipients with CF remain at risk of skeletal fragility despite prompt initiation of post-transplant anti-osteoporosis therapy.

The Phosphodiesterase Inhibitor Ensifentrine Reduces Production of Proinflammatory Mediators in Well Differentiated Bronchial Epithelial Cells by Inhibiting PDE4.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel that impair airway salt and fluid secretion. Excessive release of proinflammatory cytokines and chemokines by CF bronchial epithelium during airway infection leads to chronic inflammation and a slow decline in lung function; thus, there is much interest in finding safe and effective treatments that reduce inflammation in CF. We showed previously that the cyclic nucleotide phosphodiesterase (PDE) inhibitor ensifentrine (RPL554; Verona Pharma) stimulates the channel function of CFTR mutants with abnormal gating and also those with defective trafficking that are partially rescued using a clinically approved corrector drug. PDE inhibitors also have known anti-inflammatory effects; therefore, we examined whether ensifentrine alters the production of proinflammatory cytokines in CF bronchial epithelial cells. Ensifentrine reduced the production of monocyte chemoattractant protein-1 and granulocyte monocyte colony-stimulating factor (GM-CSF) during challenge with interleukin-1ß Comparing the effect of ensifentrine with milrinone and roflumilast, selective PDE3 and PDE4 inhibitors, respectively, demonstrated that the anti-inflammatory effect of ensifentrine was mainly due to inhibition of PDE4. Beneficial modulation of GM-CSF was further enhanced when ensifentrine was combined with low concentrations of the ß 2-adrenergic agonist isoproterenol or the corticosteroid dexamethasone. The results indicate that ensifentrine may have beneficial anti-inflammatory effects in CF airways particularly when used in combination with ß 2-adrenergic agonists or corticosteroids. SIGNIFICANCE STATEMENT: Airway inflammation that is disproportionate to the burden of chronic airway infection causes much of the pathology in the cystic fibrosis (CF) lung. We show here that ensifentrine beneficially modulates the release of proinflammatory factors in well differentiated CF bronchial epithelial cells that is further enhanced when combined with ß2-adrenergic agonists or low-concentration corticosteroids. The results encourage further clinical testing of ensifentrine, alone and in combination with ß2-adrenergic agonists or low-concentration corticosteroids, as a novel anti-inflammatory therapy for CF.

Changes in 6-minute walking distance in lung transplant candidates while participating in a home-based pre-habilitation program-A retrospective chart review.

Home-based exercise programs may offer a less costly alternative to providing exercise pre-transplant to a large number of patients. We describe the changes in 6-minute walk distance (6MWD) in lung transplant candidates who participated in a home-based exercise program and their relationship to post-transplant outcomes. Retrospectively, we investigated 159 individuals while awaiting transplantation who performed the surgery between 2011 and 2015. Primary outcome was 6MWD at time of assessment for transplant, last test prior to transplant and one-month post-transplant. 6MWD decreased by 28 ± 93.9 m between the time of assessment and the last 6MWD prior to transplantation (P < .001). Forty-one patients (25.8%) increased their 6MWD (mean + 85.8 ± 42.8 m); 72 patients (45.3%) decreased their 6MWD (mean -109.8 ± 71.2 m); and 46 patients (28.9%) had no change in 6MWD (-1.5 ± 15.7 m). There was a moderate correlation (r = .528; P < .001) between the last 6MWD prior to transplant and 6MWD post-transplant. Change in 6MWD prior to transplant weakly correlated with length of time on mechanical ventilation (r = -.185; P = .034). When adjusted for covariates, change in 6MWD prior to transplant was not associated with length of time on mechanical ventilation, total hospital LOS, or intensive care unit LOS. The majority of the patients were able to either increase or maintain their 6MWD while participating in a home-based pre-habilitation program during the waiting list period. Prospective research is needed to evaluate the effects of home-based pre-habilitation program for lung candidates.

Brief report: International perspectives on the pediatric COVID-19 experience.

The 2019 novel coronavirus (SARS-CoV-2) is endangering human health worldwide; scarcity of published pediatric cases and current literature and the absence of evidence-based guidelines necessitate international sharing of experience and personal communication. On 31 March 2020 the International Committee of the American Thoracic Society Pediatrics Assembly recorded an online podcast, during which pediatric pulmonologists worldwide shared their experience on the novel coronavirus disease (COVID-19) in children. The aim was to share personal experience in organizing pediatric care in different health care settings globally, protecting health care workers, and isolation practices. This manuscript summarizes the common themes of the podcast which centered around three main topics: more benign clinical disease and progression in pediatric cases compared to adults, a strong need for strategies to protect health care workers, and social or economic disparities as a barrier to successful pandemic control.

Comparison of oscillometry devices using active mechanical test loads.

Noninvasiveness, low cooperation demand and the potential for detailed physiological characterisation have promoted the use of oscillometry in the assessment of lung function. However, concerns have been raised about the comparability of measurement outcomes delivered by the different oscillometry devices. The present study compares the performances of oscillometers in the measurement of mechanical test loads with and without simulated breathing. Six devices (five were commercially available and one was custom made) were tested with mechanical test loads combining resistors (R), gas compliances (C) and a tube inertance (L), to mimic respiratory resistance (R rs) and reactance (X rs) spectra encountered in clinical practice. A ventilator was used to simulate breathing at tidal volumes of 300 and 700 mL at frequencies of 30 and 15 min-1, respectively. Measurements were evaluated in terms of R, C, L, resonance frequency (f res), reactance area (AX ) and resistance change between 5 and 20 or 19 Hz (R 5-20(19)). Increasing test loads caused progressive deviations in R rs and X rs from calculated values at various degrees in the different oscillometers. While mean values of R rs were recovered acceptably, some devices exhibited serious distortions in the frequency dependences of R rs and X rs, leading to large errors in C, L, f res, AX and R 5-20(19). The results were largely independent of the simulated breathing. Simplistic calibration procedures and mouthpiece corrections, in addition to unknown instrumental and signal processing factors, may be responsible for the large differences in oscillometry measures. Rigorous testing and ongoing harmonisation efforts are necessary to better exploit the diagnostic and scientific potential of oscillometry.

Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.

BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).