Inhaled Mannitol on Mucociliary Clearance in Moderate to Severe Cystic Fibrosis

Study Overview
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Brief Summary
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This study will provide important mechanistic information regarding the effect of inhaled mannitol (Bronchitol) in people with cystic fibrosis (PwCF) with moderate to severe disease who are already using elexacaftor/tezacaftor/ivacaftor (E/T/I). Many patients have already discontinued hypertonic saline and other pulmonary therapies because of the profound effect of E/T/I of their symptoms and lung function. Further, because both inhaled osmotic agents (i.e., Bronchitol, hypertonic saline [HS]) and E/T/I are believed to exert their beneficial effects through improvements in mucociliary clearance (MCC), it is unknown if the combination of these therapies might be additive or are redundant in a population with moderate to severe disease where bronchiectasis and chronic infection persists, and where eventual decline in lung function is expected over time. This study, therefore, will be the first to determine whether add on therapy with inhaled mannitol is able to further accelerate MCC in E/T/I patients. These data would provide some guidance regarding the use of these approved therapies in PwCF.

Official Title
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Effect of Bronchitol on Mucociliary Clearance in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Modulator Treated Patients With Cystic Fibrosis With Moderate to Severe Lung Disease

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Mannitol Inhalant Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide informed consent Age ≥ 18 at the time of screening Diagnosis of cystic fibrosis (CF) Regularly using elexacaftor/tezacaftor/ivacaftor (E/T/I) for ≥ 90 days FEV1 between 30% and 70%, inclusive, at time of screening Denies active smoking or vaping Clinically stable with no significant changes in health status within the 28 days prior to and including the screening visit Patients on cycled inhaled antibiotics will need to be either on or off their antibiotic for 7 days prior to Visit 1 and not scheduled to cycle during the 2-week treatment period until after Visit 2 Has no other conditions that, in the opinion of the Site Investigator/Designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives Exclusion Criteria: Use of an investigational drug within 28 days prior to and including the screening visit Unable or unwilling to withhold hypertonic saline (HS) for 4 weeks (2 weeks prior to Visit 1 and 2 weeks between Visit 1 and Visit 2) Unable or willing to withhold dornase alfa and bronchodilators on the morning of Visit 1 and Visit 2, until completion of study procedures Initiation of new chronic CF pulmonary therapy (e.g. dornase alfa, azithromycin, inhaled antibiotic) within 28 days prior to and including the screening visit No acute use of antibiotics (oral, inhaled, or intravenous) or acute use of systemic corticosteroids for respiratory tract symptoms within 28 days prior to and including the screening visit. No chronic use of oral corticosteroids > 10 mg of prednisone or equivalent daily Unable to tolerate albuterol or other bronchodilator History of intolerance to HS or inhaled mannitol Pregnancy or breast feeding Have had more than 2 chest computed tomography (CT) in the past year or a combination of procedures that are believed to have exposed the subject's lungs to >150 millisievert (mSv) History of significant hemoptysis (>60 mL) in the last three months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled Mannitol<br>All study participants will receive the same study treatment. Study treatment will be dry powder mannitol 400 mg twice a day by oral inhalation (the contents of 10 capsules administered individually) for 14 days +/- 2 days. | Drug: Mannitol Inhalant Product<br>* A sugar alcohol indicated as an add-on maintenance therapy to improve pulmonary function in adult patients 18 years of age and older with cystic fibrosis.<br>* Other names: Bronchitol; dry powder mannitol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average change in rate of mucociliary clearance (MCC) over 60 minutes from Visit 1 (pre-mannitol) to Visit 2 (post-mannitol) | The primary outcome will be the average rate of MCC measured in the whole right lung compartment over 60 minutes (MCC60), calculated using point estimates collected every 10 minutes. The change in rate of MCC over 60 minutes from Visit 1 to Visit 2 will be assessed. | Day 1 to Day 14(+/-2 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average change in cough clearance from Visit 1 (pre-mannitol) to Visit 2 (post-mannitol) | Cough clearance is measured through voluntary peak flow measurements during MCC scans. Peak flows will be obtained by utilizing a PIKO peak flow meter during a huff cough maneuver. The change in cough clearance from Visit 1 to Visit 2 will be assessed. | Day 1 to Day 14(+/-2 days) | 
| Average change in rate of mucociliary clearance (MCC) over 90 minutes from Visit 1 (pre-mannitol) to Visit 2 (post-mannitol) | Mucociliary clearance is measured in the whole right lung compartment over 90 minutes (MCC90), calculated using point estimates collected every 10 minutes. The change in MCC90 from Visit 1 to Visit 2 will be assessed. | Day 1 to Day 14(+/-2 days) | 
| Change in forced expiratory volume in one second (FEV1) % of predicted from Visit 1 to Visit 2 | FEV1 is measured by spirometry. On each occasion, the best of 3 trials, based on American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria. The best forced vital capacity (FVC), FEV1 and Forced expiratory flow between 25% and 75% of vital capacity (FEF25-75) (from trial with highest FVC+FEV1 sum) will be recorded (absolute value and % of predicted). The change in FEV1 from Visit 1 to Visit 2 will be assessed. | Day 1 to Day 14(+/-2 days) | 
| Change in respiratory symptoms as measured by the Cystic Fibrosis Respiratory Questionnaire Revised (CFQR-R) from Visit 1 to Visit 2 | The CFQ-R (Cystic fibrosis Questionnaire - Revised) is a detailed, rigorously designed and validated self-report instrument designed to measure quality of life in patients with CF who are 14 years and older. This instrument was developed as the first CF-specific, health-related Quality of Life (QOL) measure. The respiratory domain has a 0-100 scale, with higher values signifying less severe symptoms. The change in Cystic Fibrosis Questionnaire Respiratory - Revised (CFQR-R) values from Visit 1 to Visit 2 will be assessed. | Day 1 to Day 14(+/-2 days) | 
| Change in respiratory symptoms as measured by the Cystic Fibrosis Respiratory Symptom Diary and Chronic Respiratory Infection Symptom Score (CFRSD-CRISS) from Visit 1 to Visit 2 | The CFRSD-CRISS is an 8-item, patient-centered, self-report outcome measure evaluating symptom severity over the prior 24 hours in 8 domains central to CF. Each question is assigned a score from 0-4 based on the response, with zero reflecting the absence of the symptom and four reflecting that the symptoms is present 'a great deal' or 'extremely'. A summed score (range from 0-24) is converted to a 0-100 scale, where lower scores indicate fewer symptoms. | Day 1 to Day 14(+/-2 days) | 
| Change in respiratory symptoms as measured by the Treatment Satisfaction Questionnaire Measure (TSQM) from Visit 1 to Visit 2 | The TSQM is a 14-question standardize measure for assessment of self-reported treatment satisfaction and has been valued for use of inhaled medications in people with CF. The TSQM items are answered on 5- or 7-point Likert type scale and cover four domains, corresponding to distinct aspects related to the satisfaction of patients with their treatment (Effectiveness; Side effects; Convenience and Global satisfaction). The questionnaire is scored on a 0-100 scale, with higher values indicated greater satisfaction. The change in TSQM score from Visit 1 to Visit 2 will be assessed. | Day 1 to Day 14(+/-2 days) |