a prospective study to evaluate biological and clinical effects of significantly corrected cftr function

Conditions: Cystic Fibrosis

Summary: this is a prospective, multi-center observational study. the study is designed to measure the clinical effectiveness of elexacaftor, tezacaftor and ivacaftor (eti) triple combination therapy in people with one or more copies of the f508del mutation, study the effects of eti across a number of cf disease manifestations, and collect specimens for future research. subjects in the study will have one "before tct" visit within 30 days before initiation of the therapy and five "after tct" visits over a 30-month follow-up period. participants who have participated in the original promise cohort have the option of participating in a long-term extension with annual visits performed at the 42- and 54-month timepoints. the durability of the clinical and biological changes in promise can be assessed with extended follow-up, which would enable the sub-studies to consider potential clinical consequences of the biological or physiological effects being studied. this work will help to inform long term prognosis and feasibility of certain clinical trials outcomes for interventional studies and may be useful when considering research priorities in drug development. most participating sites have been divided into sub-study groups; each sub-study group has specific non-optional procedures conducted in addition to the "core" procedures. finally, there is one optional procedure (transient elastography) that will be offered to subjects at certain sites. the duration of participation for each subject is 30 months (with an additional 24 months if participants agree to the optional long-term extension). note: fda has reviewed the new drug application (nda) for elexacaftor, tezacaftor and ivacaftor and has granted approval.

cystic fibrosis (cf) is an autosomal recessive genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (cftr) protein. in people with cf, this manifests as dysfunction in multiple organ systems including the lungs, pancreas, liver, intestines, skin and others. while nearly 2000 mutations have been described, the most common disease-causing cftr mutation is f508del, which is found in \>85% of patients followed in the us cf patient registry. two cftr corrector drugs plus the potentiator ivacaftor have been developed as a triple combination therapy for cf patients with one or two copies of the f508del mutation. we predict that over 90% of cf patients (initially age 12 y/o and above) will be eligible for highly effective cftr modulator therapy in the u.s. the promise study is designed to measure the direct and indirect cftr-dependent anion secretion by collecting and analyzing clinical research outcomes and biomarkers on a large number of patients both before and after they begin treatment with elexacaftor, tezacaftor and ivacaftor triple combination therapy (tct). this study will investigate the impact of tct across a wide range of cf disease manifestations and organ systems. while specific biomarkers of special interest have been selected for detailed analysis in this study, an additional important goal is to collect blood, urine, stool, and airway epithelial cell specimens for long-term storage in a biorepository to enable future research. these samples can be made available for research beyond the current scope of work. the promise study will provide a coordinated collection of clinical research outcomes data that can be linked with these specimens.

Eligibility criteria:
inclusion criteria: 1. all genders within the age limit of the fda approved indication for elexacaftor, tezacaftor and ivacaftor triple combination therapy (tct) at day 1. 2. diagnosis of cf. 3. cftr mutations consistent with the fda approved indication for elexacaftor, tezacaftor and ivacaftor triple combination therapy (tct). 4. physician intent to prescribe elexacaftor, tezacaftor and ivacaftor triple combination therapy (tct). 5. willing to fast for 8 hours prior to all study visits (for subjects on overnight enteric tube feedings, willing to hold the feeding for at least 8 hours). 6. able to perform the testing and procedures required for this study, as judged by the investigator. 7. enrolled in the cystic fibrosis foundation patient registry. 8. clinically stable with no significant changes in health status within the 14 days prior to visit 1. exclusion criteria: 1. use of any tct within the 180 days prior to visit 1. 2. any acute use of antibiotics (oral, inhaled or iv) or systemic corticosteroids within the 2 weeks prior to visit 1 for lower respiratory tract symptoms. 3. initiation of any new chronic therapy (e.g., ibuprofen, pulmozyme®, hypertonic saline, azithromycin, inhaled tobramycin, cayston®, kalydeco, orkambi®, symdeko®) within the 4 weeks prior to visit 1. 4. use of an investigational agent within the 28 days prior to visit 1. 5. use of chronic oral corticosteroids (equivalent to 10 mg. or more per day of prednisone) within the 28 days prior to visit 1. 6. treatment for nontuberculous mycobacterial (ntm) infection, consisting of ≥ two antibiotics (oral, iv, and/or inhaled) within the 28 days prior to visit 1. 7. history of lung or liver transplantation, or listing for organ transplantation.

Keywords: cf cftr modulator triple combination therapy