Optimizing Treatments among People with Cystic Fibrosis in the Era of Highly Effective Modulator Therapy. Short title: Optimizing Treatments among PwCF.

About This Grant

Abstract (30 lines) Cystic fibrosis (CF) is a life-limiting genetic disease affecting multiple organ systems. Over the past several decades, novel therapies have driven improvements in lung function and survival. However, the burden of taking multiple treatments for people with CF (pwCF) have been substantial. The recent introduction of elexacaftor/tezacaftor/ivacaftor (ETI), a highly effective CF transmembrane conductance regulator (CFTR) modulator now used by approximately 80% of pwCF, has led to marked improvements in lung function and reductions in pulmonary exacerbations. This has prompted many pwCF and their healthcare providers to reconsider the necessity of conventional CF therapies, such as inhaled dornase alfa (DA) and hypertonic saline (HTS). While some studies have suggested that discontinuing these treatments may not immediately affect lung function, the longer-term consequences of reducing the conventional therapies remain unclear, particularly for individuals with more advanced lung disease. Additionally, ETIs have been linked to potential adverse effects including liver dysfunction and mental health issues. Robust real-world data studies are essential to understand the safety profile and variability in individual responses to guide clinical decision- making. To address these critical knowledge gaps in this rare but high-cost and -burden disease, we propose a comprehensive epidemiologic study leveraging patient registries and healthcare databases to evaluate the impact of reducing conventional CF therapies and the safety profile of ETI. We will link information in the Cystic Fibrosis Foundation Patient Registry to the healthcare database for pwCF insured by Medicaid or commercial insurances from Carelon Research to identify detailed information on genotype and phenotype, lung function, medication use, clinical outcomes, and adverse effects. The specific aims are to: (1) assess the effectiveness of adhering to conventional CF therapies among pwCF who initiated ETI; (2) identify and assess the effectiveness of an adaptive strategy, based on clinical course and pulmonary function test measures, to discontinue traditional CF medications compared to fixed strategies; and (3) assess non-pulmonary adverse events potentially associated with ETI treatment, like depression and liver disease. We have assembled an interdisciplinary team of methodological and clinical experts with prior collaboration and deep clinical and methodological experience relevant to the research questions, data sources, data linkage, and analytic methods, supported by extensive preliminary analyses demonstrating feasibility. This approach will allow us to examine the real-world outcomes of treatment discontinuation and identify optimal usage patterns of traditional CF medications based on lung function values and exacerbation history in the ETI era. Findings from this study will provide evidence-based guidance to optimize CF therapy, balancing the benefits of simplifying treatment regimens with the potential risks of medication discontinuation and drug-related complications.