Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study.

BACKGROUND: Phase 3 clinical trials showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in people with cystic fibrosis (CF) with ≥1 F508del-CFTR allele. To assess long-term effects of ELX/TEZ/IVA under real-world conditions of use, a 5-year observational registry-based study is being conducted. We report interim results from the first 2 years of follow-up. METHODS: The study included people with CF in the US Cystic Fibrosis Foundation Patient Registry (CFFPR) who initiated ELX/TEZ/IVA between October 2019 and December 2020. Pulmonary exacerbations (PEx), percent predicted forced expiratory volume in 1 second (ppFEV1), hospitalizations, bacterial pathogens, body mass index (BMI), CF complications and comorbidities, and liver function tests (LFTs) after treatment initiation were compared with the 5-year pre-treatment period. Death and lung transplantation were assessed relative to 2019 CFFPR data. RESULTS: 16,116 people with CF were included (mean treatment duration 20.4 months). Among those with 5 years of pre-treatment data, mean PEx/patient/year declined to 0.18 (95% CI: 0.17, 0.19) in Years 1 and 2 post-treatment from 0.86 (95% CI: 0.83, 0.88) in the baseline year (79% reduction), after a continued increase observed pre-treatment. Similarly, a decline in mean hospitalizations/patient/year was observed in Year 1 that was sustained in Year 2 (74% reduction from baseline year). The mean absolute change in ppFEV1 from baseline was +8.2 percentage points (95% CI: 8.0, 8.4) in Year 1 and +8.9 percentage points (95% CI: 8.7, 9.1) in Year 2, after a continued decline observed pre-treatment. Positive bacterial cultures decreased for all evaluated pathogens, and mean BMI increased by 1.6 kg/m2 (95% CI: 1.5, 1.6) by Year 2. No new safety concerns were identified based on evaluation of CF complications, comorbidities, and LFTs. The annualized rates of death (0.47% [95% CI: 0.39, 0.55]) and lung transplantation (0.16% [95% CI: 0.12, 0.22]) were considerably lower than reported in 2019 (1.65% and 1.08%, respectively). CONCLUSIONS: ELX/TEZ/IVA treatment was associated with sustained improvements in lung function, reduced frequency of PEx and all-cause hospitalization, increased BMI, and lower prevalence of positive bacterial cultures. Additionally, there was a 72% lower rate of death and 85% lower rate of lung transplantation relative to the year before ELX/TEZ/IVA availability. These results, from the largest cohort of ELX/TEZ/IVA-treated people to date, extend our understanding of the broad clinical benefits of ELX/TEZ/IVA.

Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study.

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele.

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age. Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes. Methods: In this 24-week open-label phase 3 study, children (N = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h). Measurements and Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period when compared with the pretreatment baseline. Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).

Predictors of obstructive sleep apnea severity in adenotonsillectomy candidates.

STUDY OBJECTIVES: There is uncertainty over which characteristics increase obstructive sleep apnea syndrome (OSAS) severity in children. In candidates for adenotonsillectomy (AT), we evaluated the relationship of OSAS severity and age, sex, race, body mass index (BMI), environmental tobacco smoke (ETS), prematurity, socioeconomic variables, and comorbidities. DESIGN: Cross-sectional screening and baseline data were analyzed from the Childhood Adenotonsillectomy Trial, a randomized, controlled, multicenter study evaluating AT versus medical management. Regression analysis assessed the relationship between the apnea hypopnea index (AHI) and risk factors obtained by direct measurement or questionnaire. SETTING: Clinical referral setting. PARTICIPANTS: Children, ages 5 to 9.9 y with OSAS. MEASUREMENTS AND RESULTS: Of the 1,244 children undergoing screening polysomnography, 464 (37%) were eligible (2 ≤ AHI < 30 or 1 ≤ obstructive apnea index [OAI] < 20 and without severe oxygen desaturation) and randomized; 129 (10%) were eligible but were not randomized; 608 (49%) had AHI/OAI levels below entry criteria; and 43 (3%) had levels of OSAS that exceeded entry criteria. Among the randomized children, univariate analyses showed significant associations of AHI with race, BMI z score, environmental tobacco smoke (ETS), family income, and referral source, but not with other variables. After adjusting for potential confounders, African American race (P = 0.003) and ETS (P = 0.026) were each associated with an approximately 20% increase in AHI. After adjusting for these factors, obesity and other factors were not significant. CONCLUSIONS: Apnea hypopnea index level was significantly associated with race and environmental tobacco smoke, highlighting the potential effect of environmental factors, and possibly genetic factors, on pediatric obstructive sleep apnea syndrome severity. Efforts to reduce environmental tobacco smoke exposure may help reduce obstructive sleep apnea syndrome severity. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (#NCT00560859).

A controlled trial of CPAP therapy on metabolic control in individuals with impaired glucose tolerance and sleep apnea.

STUDY OBJECTIVES: To address whether treatment of sleep apnea improves glucose tolerance. DESIGN: Randomized, double-blind crossover study. SETTING: Sleep clinic referrals. PATIENTS: 50 subjects with moderate to severe sleep apnea (AHI > 15) and impaired glucose tolerance. INTERVENTIONS: Subjects were randomized to 8 weeks of CPAP or sham CPAP, followed by the alternate therapy after a one-month washout. After each treatment, subjects underwent 2-hour OGTT, polysomnography, actigraphy, and measurements of indices of glucose control. MEASUREMENTS AND RESULTS: The primary outcome was normalization of the mean 2-h OGTT; a secondary outcome was improvement in the Insulin Sensitivity Index (ISI (0,120). Subjects were 42% men, mean age of 54 (10), BMI of 39 (8), and AHI of 44 (27). Baseline fasting glucose was 104 (12), and mean 2-h OGTT was 110 (57) mg/dL. Seven subjects normalized their mean 2-h OGTT after CPAP but not after sham CPAP, while 5 subjects normalized after sham CPAP but not after CPAP. Overall, there was no improvement in ISI (0,120) between CPAP and sham CPAP (3.6%; 95% CI: [-2.2%, 9.7%]; P = 0.22). However, in those subjects with baseline AHI ≥ 30 (n = 25), there was a 13.3% (95% CI: [5.2%, 22.1%]; P < 0.001) improvement in ISI (0,120) and a 28.7% (95%CI: [-46.5%, -10.9%], P = 0.002) reduction in the 2-h insulin level after CPAP compared to sham CPAP. CONCLUSIONS: This study did not show that IGT normalizes after CPAP in subjects with moderate sleep apnea and obesity. However, insulin sensitivity improved in those with AHI ≥ 30, suggesting beneficial metabolic effects of CPAP in severe sleep apnea. Clinical trials information: ClinicalTrials.gov Identifier: NCT01385995.

Comparative effectiveness research in obstructive sleep apnea: bridging gaps between efficacy studies and clinical practice.

Comparative effectiveness research encompasses research that compares two interventions to each other, and takes place in real-world settings without strict inclusion and exclusion criteria, according to the established standard of care. There is a need for comparative evaluations of the treatments for obstructive sleep apnea, a disease associated with increased cardiovascular risk, stroke and metabolic derangement. This article reviews the recent, representative literature that addresses obstructive sleep apnea intervention and treatment, paradigms for diagnosis and randomized control trials addressing the efficacy of interventions, in an effort to demonstrate examples of both traditional observational and randomized control trials, as well as to illustrate the considerable overlap between some traditional studies and comparative effectiveness research. Despite methodological challenges, the potentially large clinical and public health impact of obstructive sleep apnea, accompanied by considerable cost, mandates that randomized controlled trials and comparative effectiveness research be systematically applied to identify both the efficacy and effectiveness of alternative diagnosis and treatment strategies.