H. Fox

Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study

This international phase III study of inhaled dry powder mannitol was a randomised, double-blind, 26-week study, followed by a further 26-week, open-label (OL) extension. 324 cystic fibrosis (CF) patients were randomised, in a 3:2 ratio, to mannitol (400 mg b.i.d.) and control groups. The primary efficacy end-point was to determine the change in forced expiratory volume in 1 s (FEV1) over the double-blind phase. Secondary end-points included changes in forced vital capacity and pulmonary exacerbations. A significant improvement in FEV1 was seen over 26 weeks (p<0.001) and was apparent by 6 weeks, irrespective of concomitant recombinant human deoxyribonuclease (rhDNase) use. At 26 weeks, there was a significant improvement in FEV1 of 92.9 mL for subjects receiving mannitol compared with controls (change from baseline 118.9 mL (6.5%) versus 26.0 mL (2.4%); p<0.001). Improvements in FEV1 were maintained up to 52 weeks in the OL part of the study. There was a 35.4% reduction in the incidence of having an exacerbation on mannitol (p=0.045). The incidence of adverse events (AEs) was similar in both groups, although treatment-related AEs were higher in the mannitol compared with the control group. The most common mannitol-related AEs were cough, haemoptysis and pharyngolaryngeal pain. Mannitol showed sustained, clinically meaningful benefit in airway function in CF, irrespective of concomitant rhDNase use. Mannitol appears to have an acceptable safety profile for patients with CF.

Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial

Rationale Bronchiectasis is characterised by excessive production of mucus and pulmonary exacerbations. Inhaled osmotic agents may enhance mucociliary clearance, but few long-term clinical trials have been conducted. Objectives To determine the impact of inhaled mannitol on exacerbation rates in patients with non-cystic fibrosis (CF) bronchiectasis. Secondary endpoints included time to first exacerbation, duration of exacerbations, antibiotic use for exacerbations and quality of life (QOL) (St Georges Respiratory Questionnaire, SGRQ). Methods Patients with non-CF bronchiectasis and a history of chronic excess production of sputum and ≥2 pulmonary exacerbations in the previous 12 months were randomised (1:1) to 52 weeks treatment with inhaled mannitol 400 mg or low-dose mannitol control twice a day. Patients were 18–85 years of age, baseline FEV1 ≥40% and ≤85% predicted and a baseline SGRQ score ≥30. Main results 461 patients (233 in the mannitol and 228 in the control arm) were treated. Baseline demographics were similar in the two arms. The exacerbation rate was not significantly reduced on mannitol (rate ratio 0.92, p=0.31). However, time to first exacerbation was increased on mannitol (HR 0.78, p=0.022). SGRQ score was improved on mannitol compared with low-dose mannitol control (−2.4 units, p=0.046). Adverse events were similar between groups. Conclusions Mannitol 400 mg inhaled twice daily for 12 months in patients with clinically significant bronchiectasis did not significantly reduce exacerbation rates. There were statistically significant improvements in time to first exacerbation and QOL. Mannitol therapy was safe and well tolerated. Trial registration number NCT00669331.

Pooled analysis of two large randomised phase III inhaled mannitol studies in cystic fibrosis

BACKGROUND To evaluate safety and efficacy of inhaled mannitol treatment in subgroups of a large global CF population. METHODS Data were pooled from two multicentre, double-blind, randomised, controlled, parallel group phase III studies in which 600 patients inhaled either mannitol (400 mg) or control (mannitol 50 mg) twice a day for 26 weeks. RESULTS Both the mean absolute change in FEV(1) (mL) and relative change in FEV(1) by % predicted from baseline for mannitol (400 mg) versus control were statistically significant (73.42 mL, 3.56%, both p<0.001). Increases in FEV(1) were observed irrespective of rhDNase use. Significant improvements in FEV1 occurred in adults but not children (6-11) or adolescents (aged 12-17). Pulmonary exacerbation incidence was reduced by 29% (p=0.039) in the mannitol (400 mg) group. CONCLUSIONS Sustained six-month improvements in lung function and decreased pulmonary exacerbation incidence indicate that inhaled mannitol is an important additional drug in the treatment of CF.

Optimising inhaled mannitol for cystic fibrosis in an adult population.

Abstract 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. Educational aims To discuss the importance of airway clearance treatments in the management of cystic fibrosis. To describe the clinical data that supports the use of mannitol in adult patients with cystic fibrosis. To highlight the role of mannitol tolerance testing in screening for hyperresponsiveness. To provide practical considerations for patient education in use of mannitol inhaler. Key points Inhaled mannitol is a safe and effective option in adult patients with cystic fibrosis. Mannitol tolerance testing effectively screens for hyperresponsiveness prior to initiation of therapy. Physiotherapists and respiratory therapists play an integral role in the introduction and maintenance of dry powder inhalation therapy. Patient training and follow-up is important for optimising longer term adherence.

WS5.2 Inhaled dry powder mannitol in cystic fibrosis (CF): impact on pulmonary exacerbations (PEs) in the Phase III studies (CF-301 & CF-302)

WS5.1 Inhaled glutathione in cystic fibrosis M. Griese1, A. Hector2, M. Kappler2, M. Ballmann3, S. Junge3, E. Rietschel4, D. Staab5, S. van Koningsbruggen4, C. Rolinck-Werninghaus5, U. Mellis6, T. Kohnlein3, T. Wagner7, C. Corner-Rettberg8, H. Teschler6, E. Heuer9, M. Kopp10, S. Heyder11, J. Hammermann12, P. Kuster13, A. Reimann14, M. Honer14, U. Mansmann2, C. Eismann2, German IGOR-Study Group. 1University of Munich, Children’s Hospital, Munich, Germany; 2University of Munich, Munich, Germany; 3Medical School Hannover, Hannover, Germany; 4University of Cologne, Cologne, Germany; 5Charite, Berlin, Germany; 6University of Essen, Essen, Germany; 7University of Frankfurt, Frankfurt, Germany; 8University of Bochum, Bochum, Germany; 9Praxis, Hamburg, Germany; 10University of Freiburg, Freiburg, Germany; 11University of Leipzig, Leipzig, Germany; 12University of Dresden, Dresden, Germany; 13Clemenshospital, Munster, Germany; 14Mukoviszidose-Institut, Bonn, Germany

47 Bronchitol (inhaled dry powder mannitol) in adult patients with cystic fibrosis

47 Bronchitol (inhaled dry powder mannitol) in adult patients with cystic fibrosis M. Aitken1, D. Bilton2, H. Fox3, B. Charlton3, CF-301 & CF-302 Study Investigators. 1University of Washington, Division of Pulmonary and Critical Care Medicine, Seattle, United States; 2Royal Brompton Hospital & Harefield NHS Foundation Trust, Department of Respiratory Medicine, London, United Kingdom; 3Pharmaxis Ltd, Frenchs Forest, Australia

77* Phase III Study [CF-302] of inhaled dry powder mannitol (Bronchitol(tm)) in cystic fibrosis – results from the 6 month open label phase

The airways of patients with cystic fibrosis (CF) are chronically infected with bacteria, which theoretically poses a risk of microbial contamination of inhaler devices. Inhaled dry powder mannitol has been investigated in patients with CF, showing improvement in FEV1, evidence of decreasing exacerbations, and no increase in qualitative or quantitative sputum microbial growth over a 6 month period. Mannitol can be used in the microbiology laboratory as a substrate for certain bacteria in vitro, and therefore we investigated the potential risk of bacterial growth on the device after 1 week of twice daily mannitol use. Methods: Eighty-five devices from 34 CF patients (1−3 per patient returned) were analysed for microbial content after 1 week’s use. The presence of P. aeruginosa, S. aureus, MRSA, Candida, yeasts, Aspergillus, coliforms, Burkholderia and Stenotrophomonas was determined. Cultures were examined daily during the first week, then weekly until the end of the incubation period for each media. Results: There was no microbiological growth on 82/85 (96.5%) inhalers. Microbiological growth was reported in one device from each of 3 patients (S. aureus and MRSA, Aspergillus, Candida). In all 3 patients, the contaminated device was the first of 3 used, with subsequent inhalers testing negative for growth of pathogens. None of the 3 patients reported an acute pulmonary exacerbation during the 6 month trial period. Conclusions: These data suggest that contamination with CF-specific pathogens is infrequent after 1 week of use of the inhaler, the recommended duration of use. There was no increase in acute pulmonary exacerbation in patients with a contaminated device.

76 Mannitol inhaler device culture: no evidence of an increased microbiological contamination

The airways of patients with cystic fibrosis (CF) are chronically infected with bacteria, which theoretically poses a risk of microbial contamination of inhaler devices. Inhaled dry powder mannitol has been investigated in patients with CF, showing improvement in FEV1, evidence of decreasing exacerbations, and no increase in qualitative or quantitative sputum microbial growth over a 6 month period. Mannitol can be used in the microbiology laboratory as a substrate for certain bacteria in vitro, and therefore we investigated the potential risk of bacterial growth on the device after 1 week of twice daily mannitol use. Methods: Eighty-five devices from 34 CF patients (1−3 per patient returned) were analysed for microbial content after 1 week’s use. The presence of P. aeruginosa, S. aureus, MRSA, Candida, yeasts, Aspergillus, coliforms, Burkholderia and Stenotrophomonas was determined. Cultures were examined daily during the first week, then weekly until the end of the incubation period for each media. Results: There was no microbiological growth on 82/85 (96.5%) inhalers. Microbiological growth was reported in one device from each of 3 patients (S. aureus and MRSA, Aspergillus, Candida). In all 3 patients, the contaminated device was the first of 3 used, with subsequent inhalers testing negative for growth of pathogens. None of the 3 patients reported an acute pulmonary exacerbation during the 6 month trial period. Conclusions: These data suggest that contamination with CF-specific pathogens is infrequent after 1 week of use of the inhaler, the recommended duration of use. There was no increase in acute pulmonary exacerbation in patients with a contaminated device.