Comparison of inhaled mannitol, daily rhDNase and a combination of both in children with cystic fibrosis: a randomised trial

Abstract

Background: Osmotic agents, such as inhaled dry powder mannitol, may increase mucociliary clearance by rehydrating the airway surface liquid and thus act as disease-modifying treatments in cystic fibrosis (CF). This is the first therapeutic trial of inhaled mannitol in children with CF; it was compared with recombinant human deoxyribonuclease (rhDNase), the current best established mucolytic treatment. Methods: 38 children were recruited to an open crossover study. Subjects underwent an initial bronchial provocation challenge with dry powder mannitol. Those children with a negative challenge were randomly allocated to one of three consecutive 12-week treatment blocks (inhaled mannitol alone, nebulised rhDNase alone and mannitol + rhDNase). The primary outcome was forced expiratory volume in 1 s (FEV 1 ). A number of secondary outcome measures were also studied. Results: Twenty children completed the study. Bronchoconstriction and cough associated with mannitol administration contributed to the high attrition rate. The mean increase in FEV 1 following 12 weeks of treatment was 0.11 litres (6.7%) (p = 0.055) for mannitol alone, 0.12 litres (7.2%) (p = 0.03) for rhDNase alone and 0.03 litres (1.88%) (p = 0.67) for rhDNase and mannitol. None of the secondary clinical outcomes was statistically significantly different between treatments. Conclusions: Inhaled mannitol was at least as effective as rhDNase after 3 months treatment. There was a marked individual variation in tolerance to mannitol and in response to treatment however. Children who do not respond to rhDNase many benefit from a trial of inhaled mannitol. The combination of mannitol and rhDNase was not useful. Trial registration number: NCT00117208Many processes contribute to airway obstruction and progressive lung damage in cystic fibrosis (CF), including the production of abnormally viscid mucus, mucus hypersecretion and defective mucociliary clearance (MCC). Previous therapeutic approaches aimed at improving airway clearance have included suppression or eradication of bacterial infection and attenuation of inflammation. Mucolytic agents have also been used to reduce sputum viscosity. Recombinant human deoxyribonuclease (rhDNase) is a now a well established and widely used adjunctive treatment for CF. DNA derived from neutrophil degradation is present in very high concentrations in the sputum of patients with CF and is a major contributor to the viscosity of airway secretions. rhDNase cleaves this extracellular DNA, improving mucus rheology. Several studies have now clearly demonstrated improvements in lung function and fewer chest exacerbations in patients treated with rhDNase.1-3 It may also reduce neutrophilic airway inflammation. 4 There is widespread variation in the individual responses to rhDNase, 3 5 however, and a significant number of patients derive no clinical benefit.Epithelial airway surface liquid (ASL) volume regulation is critical for normal MCC, and airway dehydration is now thought to be a key initiating event in the pathogenesi...

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

“…The additional benefit of mannitol over the study period was very similar in rhDNase users and nonusers when compared with control; this is in contrast with a recent, small phase II study [23], which suggested that the combined use of rhDNase and mannitol may not result in greater improvement than rhDNase alone. The present larger study demonstrated that mannitol offered an additional lung function benefit on top of rhDNase as part of standard therapy and confirms its applicability to a wide range of CF patients.…”

New Pulmonary Therapies Directed at Targets Other than CFTR

“…During 6 mo of double-blinded treatment, mannitol led to an average 7.3% improvement in FEV 1 compared to baseline ( p , 0.001), and a similar significant improvement when compared to placebo treatment ( p , 0.001). In contrast to data from a small study by Minasian et al (2010), patients using rhDNase with mannitol also showed lung function improvement (FEV 1 5.3%; p , 0.001), although this was numerically smaller than the FEV 1 change in those not using rhDNase (9.44% improvement from baseline). The effect of mannitol on pulmonary exacerbations appears to be smaller than that reported by Elkins et al (2006) in their study of HS.…”

Physicochemical Characterization of Nebulized Superparamagnetic Iron Oxide Nanoparticles (SPIONs)

“…(30,31) The desirability of using nebulized mannitol is largely a result of its minimal airway transepithelial permeability, resulting in a longer duration of therapeutic action, as well as its pleasant taste and mouth feel for encouraging patient use. (32,33) Aerosolized Rienso particles were also captured on a TEM grid and analyzed to compare with the Rienso particles in the suspension. Image analysis of aerosolized Rienso particles by TEM demonstrated an overall pattern of monodispersed spherical particles, comprised of agglomerates of primary particles (Fig.…”