Inhaled Mannitol for Cystic Fibrosis

Recruiting in Palo Alto (17 mi)

Overseen by Subhashini A Sellers, MD, MSCR

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: University of North Carolina, Chapel Hill

Must be taking: Elexacaftor/tezacaftor/ivacaftor

Must not be taking: Investigational drugs, Hypertonic saline

Disqualifiers: Pregnancy, Breastfeeding, Significant hemoptysis, others

No Placebo Group

Prior Safety Data

Approved in 5 Jurisdictions

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires participants to stop using hypertonic saline for 4 weeks and to withhold dornase alfa and bronchodilators on the morning of certain visits. Participants must also not start new chronic CF pulmonary therapies or use certain antibiotics and corticosteroids shortly before and during the trial.

What data supports the effectiveness of the drug inhaled mannitol for cystic fibrosis?

Research shows that inhaled mannitol helps improve lung function and clears mucus in people with cystic fibrosis. Studies found it safe and effective, with significant improvements in lung health and quality of life for both adults and children. ^{1 2 3 4 5}

Is inhaled mannitol safe for humans?

Inhaled mannitol, also known as Bronchitol, has been shown to be safe for use in adults with cystic fibrosis. Clinical studies confirm its safety, although a small number of patients may not tolerate it well. Proper inhaler technique and clear expectations can improve tolerance and adherence. ^{1 2 3 5 6}

How is inhaled mannitol different from other cystic fibrosis treatments?

Inhaled mannitol is unique because it is administered as a dry powder inhaler, which helps to draw water into the airways, making mucus less sticky and easier to clear. This mechanism of action is different from other treatments that may focus on breaking down mucus or reducing inflammation. ^{7 8 9 10 11}

Eligibility Criteria

Adults over 18 with cystic fibrosis who've been on elexacaftor/tezacaftor/ivacaftor for at least 90 days, have an FEV1 between 30-70%, and are non-smokers. They must be stable health-wise and not on certain other treatments or medications that could affect the trial results.

Inclusion Criteria

I am 18 years old or older.

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

Able to provide informed consent

Exclusion Criteria

Use of an investigational drug within 28 days prior to and including the screening visit

I can stop using hypertonic saline for 4 weeks.

You cannot tolerate albuterol or other medicines that help open up the airways.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive dry powder mannitol 400 mg twice a day by oral inhalation for 14 days

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Mannitol Inhalant Product (Osmotic Agent)

Trial Overview The study is testing if adding inhaled mannitol (Bronchitol) to patients' current regimen of elexacaftor/tezacaftor/ivacaftor can further improve mucociliary clearance in those with moderate to severe cystic fibrosis.

Participant Groups

Group I: Inhaled Mannitol Experimental Treatment 1 Intervention

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.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of North Carolina at Chapel Hill Chapel Hill, NC

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill Lead Sponsor

Chiesi USA, Inc. Industry Sponsor

References

1. England pubmed.ncbi.nlm.nih.gov

Optimising inhaled mannitol for cystic fibrosis in an adult population. [2020] There has been remarkable progress in the treatment of cystic fibrosis (CF) patients over the past 20 years. However, limitations of standard therapies have highlighted the need for a convenient alternative treatment to effectively target the pathophysiologic basis of CF-related disease by improving mucociliary clearance of airway secretions and consequently improve lung function and reduce respiratory exacerbations. Mannitol is an osmotic agent available as a dry powder, dispensed in a convenient disposable inhaler device for the treatment of adult patients with CF. Inhalation of mannitol as a dry powder is thought to change the viscoelastic properties of airway secretions, increase the hydration of the airway surface liquid and contribute to increased mucociliary and cough clearance of retained secretions. In two large phase 3 studies [1, 2], long-term use of inhaled mannitol resulted in a significant and clinically meaningful improvement in lung function relative to control in adult CF subjects and had an acceptable safety profile. Clinical experience with inhaled mannitol confirms that it is safe and effective. A minority of patients are unable to tolerate the medication. However, through training in proper inhaler technique and setting clear expectations regarding therapeutic effects, both the tolerance and adherence necessary for long term efficacy can be positively influenced.

2. New Zealand pubmed.ncbi.nlm.nih.gov

Cost Effectiveness of Inhaled Mannitol (Bronchitol®) in Patients with Cystic Fibrosis. [2020] Label="BACKGROUND">Inhaled mannitol (Bronchitol®) is licensed in Australia as a safe and efficacious addition to best supportive care in patients with cystic fibrosis.

3. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study. [2022] Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults.

4. Netherlands pubmed.ncbi.nlm.nih.gov

Inhaled dry powder mannitol in children with cystic fibrosis: A randomised efficacy and safety trial. [2018] Inhaled mannitol has beneficial effects on lung function, mucociliary clearance, quality of life and sputum properties. This trial examined the efficacy of inhaled mannitol in children with cystic fibrosis (CF).

5. Netherlands pubmed.ncbi.nlm.nih.gov

Inhaled mannitol in patients with cystic fibrosis: A randomised open-label dose response trial. [2013] Cystic fibrosis (CF) is characterised by impaired mucociliary clearance (MCC), chronic inflammation and infection, and progressively deteriorating lung function. Inhaled mannitol (Bronchitol) has been shown to increase MCC and cough clearance and FEV(1) in CF patients, contributing to better lung hygiene and consequently a slower decline in lung function. This study was designed to determine the dose relationship of mannitol treatment and improvement in FEV(1) and FVC as well as safety.

6. Netherlands pubmed.ncbi.nlm.nih.gov

Safety assessment of inhaled xylitol in subjects with cystic fibrosis. [2013] Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration, thus enhancing innate immunity. We tested the safety and tolerability of aerosolized iso-osmotic xylitol in subjects with cystic fibrosis.

7. England pubmed.ncbi.nlm.nih.gov

Glycopyrrolate/formoterol fumarate metered dose inhaler for maintenance-naïve patients with chronic obstructive pulmonary disease: a post-hoc analysis of the randomized PINNACLE trials. [2020] Glycopyrrolate (GP)/formoterol fumarate (FF; GFF) metered dose inhaler is a fixed-dose combination dual bronchodilator for patients with chronic obstructive pulmonary disease (COPD); however, whether the efficacy in patients without current maintenance treatment is consistent with currently maintenance-treated patients is unclear.

8. England pubmed.ncbi.nlm.nih.gov

Real-life therapeutic effects of beclomethasone dipropionate/formoterol fumarate/glycopyrronium combined triple therapy in patients with chronic obstructive pulmonary disease. [2023] The small airway disease has been recognized as a central feature of chronic obstructive pulmonary disease (COPD). Triple fixed combination beclomethasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) is provided as a pressurized single-dose inhaler based on an extra-fine formulation, which has been approved for patients with COPD experiencing frequent disease exacerbations.

9. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of glycopyrronium/formoterol fumarate dihydrate delivered via metered dose inhaler using co-suspension delivery technology in patients with moderate-to-very severe COPD. [2018] Label="Purpose">The efficacy and tolerability of GFF MDI (Bevespi Aerosphere®), a fixed-dose combination of glycopyrronium (GP)/formoterol fumarate dihydrate (FF) 14.4/10 μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 μg) delivered by metered dose inhaler (MDI) using innovative co-suspension delivery technology, has been investigated in a Phase III clinical trial program (NCT01854645, NCT01854658, NCT01970878) in patients with COPD. Here, we present findings from a pharmacokinetic (PK) sub-study of NCT01854645 (PINNACLE-1).

10. India pubmed.ncbi.nlm.nih.gov

Comparative efficacy and safety of glycopyrronium/formoterol fixed-dose combination versus glycopyrronium monotherapy in patients with moderate-to-severe COPD. [2023] The safety and efficacy of fixed-dose combination (FDC) of glycopyrronium bromide 12.5 μg/formoterol fumarate 12 μg (GB/FF) twice daily as dry powder inhalers (DPIs) compared to glycopyrronium 50 μg monotherapy (GLY) once daily as DPI in subjects with moderate-to-severe chronic obstructive pulmonary disease (COPD) were evaluated.

11. England pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of glycopyrrolate/formoterol metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with chronic obstructive pulmonary disease. [2022] The long-term safety and efficacy of a novel Co-Suspension™ Delivery Technology glycopyrrolate (GP)/formoterol fumarate (FF) 18/9.6 μg fixed-dose combination metered dose inhaler (GFF MDI) were investigated in a 28-week safety extension study (PINNACLE-3, NCT01970878) of two randomized controlled Phase III trials (PINNACLE-1 and -2; NCT01854645 and NCT01854658) in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD).