Symptom Based Performance of Airway Clearance After Starting Highly Effective Modulators for Cystic Fibrosis (SPACE-CF)

Cystic Fibrosis (CF) is an autosomal recessive disease cause by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) manifesting in multiple organs, the most common cause of morbidity and mortality continues to be the pulmonary manifestation. CFTR dysfunction leads to reduced mucociliary clearance, impaired innate immune system function in the lungs (within the airway surface liquid \[ASL\] lining the epithelial barrier of the lungs) and reduced ASL hydration (stickier mucus). To try and help correct this underlying defect patients have been performing airway clearance for decades using different techniques (Percussion and postural drainage \[P\&PD\], Positive expiratory pressure \[PEP\], Oscillatory positive expiratory pressure \[OPEP\], High-frequency chest compression \[HFCC\], exercise), inhaled mucolytics (Hypertonic Saline, Pulmozyme) and inhaled antibiotics. However, performing daily airway clearance can be a large burden on patients and their families with a median number of daily therapies around 7 and average time spent on therapies at almost 2 hours daily. This high treatment burden leads many patients to have reduced adherence to their regimens and multiple studies have shown around 20% of patients performing no daily airway clearance. Since the release of highly effective CFTR modulator therapy patients have experienced improvements in lung function measurements and imaging-based ventilation measurements, reduction in pulmonary exacerbations, and improvement in daily symptom scores. Over 80% of patients and their families and over 95% of clinicians in the United States support the idea of trials looking into the simplification of airway clearance regimens. Combining the inability of most patients to complete their daily regimens, patient and clinician interest in treatment simplification research, and the overwhelming cost of most inhaled medications in cystic fibrosis with the improvement in mucociliary transport and symptoms with highly effective modulator therapy suggests a research program aimed at reducing the treatment burden of daily airway clearance should be considered. The investigators propose the following: determine if there is additional benefit in continuous airway clearance regimens after starting Elexacaftor-Tezacaftor-Ivacaftor (ETI) and if so, is this benefit noticeable on pulmonary function testing and imaging.

This will be a randomized controlled trial design with 2:1 randomization (2 to symptom driven to 1 in continuous) for this pilot study to determine if symptom-driven airway clearance after starting Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy is feasible and can eventually determine if it is non-inferior to continuing airway clearance therapies. The study will be performed as an intention to treat protocol. All participants who are eligible and enrolled will be asked to perform airway clearance twice daily for 12 weeks prior to randomization and then will be followed for 12 weeks including study visits at week 0, week 4, week 8, and week 12. The study will require no change in current use of inhaled antibiotics nor adjust the frequency of the medication during the study. Airway clearance methods to be recorded include aerobika or flutter valve, high frequency chest oscillation therapy (vest), intrapulmonary percussive ventilator, or exercise performed specially for airway clearance. The medications to be monitored included nebulized Albuterol, nebulized hypertonic saline, nebulized Pulmozyme, and nebulized mannitol. The continuous arm (control arm) will be asked to perform airway clearance twice daily for the entirety of the study and record all therapies performed daily. The symptom driven arm will perform airway clearance on their own discretion, whether this be from steady decline in baseline respiratory status or acute flair of symptoms related to infectious etiology. At baseline participants will undergo pulmonary function testing, sputum/throat culture and Cystic Fibrosis Questionnaire Revise (CFQ-R). On week 0, week 4, week 8 and week 12 visits the participants will undergo pulmonary function testing and CFQ-R with addition of sputum/throat cultures on week 12. Between each study visit participants will be asked to perform home spirometry once weekly for the 12-week trial period. For participants enrolled in the continuous group the investigators will ask for participants to perform home spirometry after either twice daily airway clearance routine or for the symptom-based group to perform at roughly the same time of day for each test. Participants will also be asked to keep a daily cystic fibrosis diary during the run-in period and study period in which participants will record if, and how frequent, participants use any airway clearance medications or devices during the day. A reduction in percent predicted forced expiratory volume in 1 second (ppFEV1%) or percent predicted forced vital capacity (ppFVC%) of more than 10% in laboratory PFT testing for 2 consecutive weeks will be deemed an adverse event and lead to the participant in the symptom driven arm being instructed to perform daily airway clearance therapy. A reduction in ppFEV1% and/or ppFVC% in home spirometry by more than 10% will trigger a need for in lab PFT testing to determine if participants have developed an adverse event leading to performing daily airway clearance therapy or if participants are to continue symptom-based airway clearance. Other criteria for participants to be evaluate in-person between study visits include use of daily airway clearance for more than 7 consecutive days in the symptom-based arm or signs and symptoms of a possible acute pulmonary exacerbation. If participants develop an exacerbation from an identifiable cause other than their primary CF lung disease (viral infection, asthma exacerbation, pulmonary embolism, etc.) participants will undergo appropriate treatment, and while the event will be deemed an adverse event, participants will continue with their current treatment protocol. Participants who are treated for an acute severe pulmonary exacerbation requiring IV antibiotics and/or hospitalization will either continue in the continuous treatment arm or if in the symptom driven arm be instructed to perform daily airway clearance for the duration of the study. In participants with concurrent asthma diagnoses, the investigators will not require any discontinuation of additional inhaler/nebulized therapies that are asthma specific, but no bronchodilators will be started specifically for the study.

Eligibility Criteria:
Inclusion Criteria:

* age \> 18 years at the time of recruitment
* treatment with Elexacaftor-Tezacaftor-Ivacaftor for \> 90 days prior to enrollment
* willing to continue twice daily airway clearance for a minimum of 90 days and up to180 days if enrolled in the continuing treatment arm
* no exacerbations in the last 28 days

Exclusion Criteria:

* active smoking or vaping (tobacco, marijuana, recreational drugs)
* recent change in chronic airway clearance regimen with the last 28 days
* inability to tolerate airway clearance or intolerance to either/or hypertonic saline and Pulmozyme
* current treatment for an acute pulmonary exacerbation
* ongoing therapy for Nontuberculous Mycobacterium (NTM)
* investigational drug use