Inhaled Mannitol for Cystic Fibrosis

Overseen By Margret Powell

Age: 18+

Sex: Any

Trial Phase: Phase 4

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 All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 2 weeks

25 Participants Needed

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}

Research Team

Subhashini A Sellers, MD, MSCR

Principal Investigator

University of North Carolina, Chapel Hill

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

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

I will not start or stop inhaled antibiotics 7 days before my first visit and won't change them for 2 weeks after.

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.

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

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.

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

Chiesi USA, Inc.

Industry Sponsor

Trials

9

Recruited

6,100+

Findings from Research

Inhaled mannitol is a safe and effective treatment for adult patients with cystic fibrosis, showing significant improvements in lung function in large phase 3 studies.

Proper training in inhaler technique and setting clear expectations can enhance patient tolerance and adherence to mannitol therapy, which is crucial for long-term efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimising inhaled mannitol for cystic fibrosis in an adult population. Flume, PA., Aitken, ML., Bilton, D., et al.[2020]

Inhaled mannitol (Bronchitol®) is a cost-effective treatment for cystic fibrosis when added to best supportive care, with a cost of AU$39,165 per quality-adjusted life-year, making it a viable option for the Australian healthcare system.

The analysis was based on a comprehensive model using data from phase III trials and Australian CF registries, showing that 77% of simulations indicated mannitol's cost-effectiveness below the AU$45,000 threshold for life-threatening diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost Effectiveness of Inhaled Mannitol (Bronchitol®) in Patients with Cystic Fibrosis. Warren, E., Morgan, K., Toward, TJ., et al.[2020]

In a study involving 423 adults with cystic fibrosis, inhaling 400 mg of mannitol twice daily for 26 weeks significantly improved lung function (FEV1) compared to a control group, with an average increase of 54 mL.

Mannitol was found to have a good safety profile, with most adverse events being mild or moderate, and only a slightly higher percentage of treatment-related adverse events compared to the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study. Flume, PA., Amelina, E., Daines, CL., et al.[2022]

Inhaled mannitol significantly improved lung function in children with cystic fibrosis, showing a 3.42% increase in ppFEV1 compared to placebo, based on a study of 92 participants aged 6-17 years.

The treatment was well tolerated, with a 30% lower incidence of pulmonary exacerbations in the mannitol group, indicating its potential safety and efficacy in managing cystic fibrosis symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled dry powder mannitol in children with cystic fibrosis: A randomised efficacy and safety trial. De Boeck, K., Haarman, E., Hull, J., et al.[2018]

Inhaled mannitol (400mg b.i.d.) significantly improved lung function in cystic fibrosis patients, showing a dose-dependent increase in FEV1 and FVC, with the highest dose resulting in an 8.75% increase in FEV1 compared to a negligible effect from the lowest dose (40mg).

The safety profile of the 400mg dose was comparable to lower doses, indicating that it is a safe and effective treatment option for improving lung hygiene and function in cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled mannitol in patients with cystic fibrosis: A randomised open-label dose response trial. Teper, A., Jaques, A., Charlton, B.[2013]

A pilot study involving 6 subjects with cystic fibrosis found that inhaling aerosolized iso-osmotic xylitol was well tolerated, with no significant changes in lung function (FEV1) or respiratory symptoms after exposure.

The study showed that xylitol did not affect serum osmolarity, electrolytes, or cytokine levels in sputum, indicating that while it is safe for short-term use, further research is needed to assess its long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety assessment of inhaled xylitol in subjects with cystic fibrosis. Durairaj, L., Launspach, J., Watt, JL., et al.[2013]

In a study involving 4,983 patients with COPD, those not on maintenance treatment (NMT) showed significant lung function improvements with the glycopyrrolate/formoterol fumarate (GFF) inhaler compared to placebo and other treatments, with a notable increase in forced expiratory volume (FEV1).

GFF also reduced the risk of clinically important deterioration (CID) and decreased the need for rescue medication in both NMT and maintenance-treated (MT) patients, demonstrating its efficacy as a first-line treatment without compromising safety.

NCBI (Pubmed)

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. Zheng, J., Xu, JF., Jenkins, M., et al.[2020]

In a real-life study of 22 COPD patients over 12 months, the triple inhaled therapy BDP/FF/G significantly improved lung function, including forced expiratory flow and reduced airway resistance, indicating its efficacy in managing small airway disease.

Patients also reported better respiratory symptoms and health status, with significant improvements in dyspnea and reduced exacerbation rates, supporting the therapy's effectiveness beyond controlled trial settings.

NCBI (Pubmed)

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. Pelaia, C., Procopio, G., Rotundo, FL., et al.[2023]

In a Phase III clinical trial involving 2,103 patients with COPD, the pharmacokinetic sub-study showed that the combination inhaler GFF MDI (glycopyrronium/formoterol) had similar plasma concentration profiles to its individual components, indicating effective delivery of both medications.

The study found that there were no significant drug-drug interactions between glycopyrronium and formoterol when administered together in GFF MDI, suggesting that the co-suspension delivery technology is safe and effective for patients.

NCBI (Pubmed)

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. Ferguson, GT., Rodriguez-Roisin, R., Reisner, C., et al.[2018]

The fixed-dose combination of glycopyrronium bromide and formoterol (GB/FF) administered twice daily significantly improved lung function in COPD patients compared to glycopyrronium monotherapy, with a notable increase in peak FEV1 after 12 weeks of treatment.

Both treatment groups experienced similar rates of adverse events, indicating that GB/FF is safe and well tolerated for patients with moderate-to-severe COPD.

NCBI (Pubmed)

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. Salvi, S., Jain, MK., Krishnamurthy, S., et al.[2023]

The GFF MDI (glycopyrrolate/formoterol fumarate) combination inhaler demonstrated long-term safety and tolerability over 52 weeks in patients with moderate-to-very severe COPD, with no unexpected safety issues reported among 892 subjects.

Efficacy results showed that GFF MDI significantly improved lung function (measured by FEV1) and reduced the need for rescue medication compared to individual components and open-label tiotropium, indicating its effectiveness as a treatment option.

NCBI (Pubmed)

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. Hanania, NA., Tashkin, DP., Kerwin, EM., et al.[2022]

References

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

Optimising inhaled mannitol for cystic fibrosis in an adult population. [2020]

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

Cost Effectiveness of Inhaled Mannitol (Bronchitol®) in Patients with Cystic Fibrosis. [2020]

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]

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

Inhaled dry powder mannitol in children with cystic fibrosis: A randomised efficacy and safety trial. [2018]

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

Inhaled mannitol in patients with cystic fibrosis: A randomised open-label dose response trial. [2013]

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

Safety assessment of inhaled xylitol in subjects with cystic fibrosis. [2013]

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]

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]

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]

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]

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]