Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from a 192-week open-label extension study.

BACKGROUND: In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. METHODS: In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del-F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. RESULTS: At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV1) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV1 % pred was +0.07 (95% CI -0.12-0.26) percentage points among the participants. CONCLUSIONS: ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.

Accounting for selection bias due to death in estimating the effect of wealth shock on cognition for the Health and Retirement Study.

The Health and Retirement Study (HRS) is a longitudinal study of U.S. adults enrolled at age 50 and older. We were interested in investigating the effect of a sudden large decline in wealth on the cognitive ability of subjects measured using a dataset provided composite score. However, our analysis was complicated by the lack of randomization, time-dependent confounding, and a substantial fraction of the sample and population will die during follow-up leading to some of our outcomes being censored. The common method to handle this type of problem is marginal structural models (MSM). Although MSM produces valid estimates, this may not be the most appropriate method to reflect a useful real-world situation because MSM upweights subjects who are more likely to die to obtain a hypothetical population that over time, resembles that would have been obtained in the absence of death. A more refined and practical framework, principal stratification (PS), would be to restrict analysis to the strata of the population that would survive regardless of negative wealth shock experience. In this work, we propose a new algorithm for the estimation of the treatment effect under PS by imputing the counterfactual survival status and outcomes. Simulation studies suggest that our algorithm works well in various scenarios. We found no evidence that a negative wealth shock experience would affect the cognitive score of HRS subjects.

Bayesian additive regression trees and the General BART model.

Bayesian additive regression trees (BART) is a flexible prediction model/machine learning approach that has gained widespread popularity in recent years. As BART becomes more mainstream, there is an increased need for a paper that walks readers through the details of BART, from what it is to why it works. This tutorial is aimed at providing such a resource. In addition to explaining the different components of BART using simple examples, we also discuss a framework, the General BART model that unifies some of the recent BART extensions, including semiparametric models, correlated outcomes, and statistical matching problems in surveys, and models with weaker distributional assumptions. By showing how these models fit into a single framework, we hope to demonstrate a simple way of applying BART to research problems that go beyond the original independent continuous or binary outcomes framework.

Trends in length of stay, functional outcomes, and discharge destination stratified by disease type for inpatient rehabilitation in Singapore community hospitals from 1996 to 2005.

OBJECTIVE: To determine the trends in length of stay (LOS), rehabilitation functional outcome, and discharge destination of patients admitted for inpatient rehabilitation from 1996 to 2005 and stratified by disease in Singapore. DESIGN: Retrospective national data were extracted from medical records of community-based inpatient rehabilitation admissions in Singapore from 1996 to 2005. SETTING: Four community hospitals. PARTICIPANTS: There were 12,506 first admissions for rehabilitation; 40.6% were for stroke, 30.4% for fracture, 2.9% for lower limb (LL) joint replacement, 2.3% for LL amputation, 1.9% for cancer, 1.8% for falls, 1.6% for pneumonia, and 18.5% for other illnesses. The overall mean age ± SD was 73.2±11.5 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: LOS, rehabilitation outcomes (rehabilitation effectiveness [R-effectiveness], rehabilitation efficiency [R-efficiency], relative functional efficiency [Relative-FE]), and discharge destination. RESULTS: The overall median LOS for all disease groups decreased by 16.2% (37 to 31d) from 1996 to 2005. The sharpest decline in LOS among the 8 disease groups was observed in the LL amputation group. The overall mean ± SD admission and discharge activities of daily living scores were 45.6±25.7 and 60.3±28.9, respectively; median R-effectiveness was 28.8%, median R-efficiency was 12.9/30d, and median Relative-FE was 27.7%/30d. From 1996 to 2005, mean R-effectiveness increased by 184% (14% to 40%), R-efficiency increased by 104% (9 to 19 units/30d), and Relative-FE increased by 145% (21% to 51%/30d). Among all inpatient admissions, most were discharged home (78.2%), 10.9% were discharged to an acute hospital, and 9.8% were discharged to nursing or sheltered homes, with no significant change during the 10-year period. CONCLUSIONS: Rehabilitation outcomes of patients admitted to Singapore's community hospitals have improved between 1996 and 2005 despite a decreasing LOS. Discharge destinations have largely remained unchanged over this period.