A PROSPECTIVE OBSERVATIONAL STUDY OF THE IMPACT OF TC CFTR THERAPY IN SEVERE DISEASE

Background: In a phase 3 clinical trial, the combination of elexacaftor/ tezacaftor/ivacaftor, triple combination therapy (TCT), resulted in significant improvements in lung function in people with cystic fibrosis (PwCF) with at least one F508del mutation Phase 3 study enrollment excluded those with severe CF lung disease, defined by percent predicted forced expiratory volume in 1 second (ppFEV1) \u003e40% This group makes up an important cohort of those living with CF who require complicated medical decision making We sought to define the clinical response to TCT in this understudied cohort Study Design: This study is a non-randomized, single-center, prospective observational study designed to evaluate clinical response in those with severe CF lung disease who initiated therapy with TCT The primary endpoint of the study is change in ppFEV1 from baseline at 1 month following initiation of TCT Secondary endpoints include ppFEV1 change at subsequent time points, adverse events, occurrence of pulmonary exacerbations, CFQ-R respiratory domain score, and change in BMI Study visits are completed at baseline, 1, 6, 9 and 12 months Assuming a 5% improvement in ppFEV1 on TCT, a sample size of 7 has 95% power to detect a 5% absolute change in ppFEV1 with an estimated standard deviation of 3 and a significance level of 0 05 using two-sided paired t-test We plan to enroll a max of 10 patients to account for screen failures but will replace subjects to maintain a sample size of 7 Interim statistical analysis was completed using 1-sample t-test, final analysis planned with 2-sample t-test Interim Results: At the time of submission, we have recruited 8 patients, 4 of whom have received TCT through commercial means (Table) Of those 4, there was a mean improvement at 1 month in ppFEV1 of 4 75% predicted, p=0 036, 95% CI (0 57, 8 93) There was a mean increase in BMI at 1 month of 0 73, p=0 0046, 95% CI (0 42, 1 03) Mean CFQ-R respiratory domain score was unchanged at 1 month An adverse event of rash occurred in 1 of 4 subjects Discussion: Interim study results of a prospective observation study in adults with CF treated with TCT who have severe pulmonary disease demonstrate improvement in lung function and BMI We expect to observe sustained pulmonary and nutritional status improvement over the 3-, 6-, 9-, and 12-month visits with ongoing use of TCT Reported adverse effects are limited to date, and there have been no study discontinuations Recruiting for this trial has restarted after the temporary halt resulting from the COVID-19 pandemic, and at the time of the conference we additionally hope to be able to include data from subjects who received non-commercial TCT