Several agents are used to clear secretions from the airways of people with
cystic fibrosis. Inhaled dry
powder mannitol is now available in Australia and some countries in Europe. The exact mechanism of action of
mannitol is unknown, but it increases mucociliary clearance. Phase III trials of inhaled dry
powder mannitol for the treatment of
cystic fibrosis have been completed. The dry
powder formulation of
mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser.
OBJECTIVES: Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies.
MAIN RESULTS: The searches identified nine separate studies (45 publications), of which four studies (36 publications) were included with a total of 667 participants, one study (only available as an abstract) is awaiting assessment and two studies are ongoing.
Duration of treatment in the included studies ranged from two weeks to six months with open-label treatment for an additional six months in two of the studies. Three studies compared
mannitol with control (a very low dose of
mannitol or non-respirable
mannitol); two of these were parallel studies with a similar design and data could be pooled, where data for a particular outcome and time point were available; also, one short-term cross-over study supplied additional results. The fourth study compared
mannitol to
dornase alfa alone and to
mannitol plus
dornase alfa. There was generally a low risk of bias in relation to randomisation and blinding; evidence from the parallel studies was judged to be of low to moderate quality and from the cross-over studies was judged to be of low to very low quality. While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the
drug's manufacturer and the author of one of the studies. There was an initial test to see if participants tolerated
mannitol, with only those who could tolerate the
drug being randomised to the studies; therefore the study results are not applicable to the
cystic fibrosis population as a whole.For the comparison of
mannitol and control, we found no consistent differences in health-related quality of life in any of the domains, except for burden of treatment, which was less for
mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. Up to and including six months, lung function in terms of forced expiratory volume at one second (millilitres) and per cent predicted were significantly improved in all three studies comparing
mannitol to control. Beneficial results were observed in these studies in adults and in both concomitant
dornase alfa users and non users. A significant reduction was shown in the incidence of pulmonary exacerbations in favour of
mannitol at six months; however, the estimate of this effect was imprecise so it is unclear whether the effect is clinically meaningful.
Cough, haemoptysis,
bronchospasm, pharyngolaryngeal
pain and post-tussive
vomiting were the most commonly reported side effects on both treatments.
Mannitol was not associated with any increase in isolation of bacteria over a six-month period.In the 12-week cross-over study (28 participants), no significant differences were found in the recorded domains of health-related quality of life or measures of lung function between
mannitol versus
dornase alfa alone and versus
mannitol plus
dornase alfa. There seemed to be a higher rate of pulmonary exacerbations in the
mannitol plus
dornase alfa arm compared with
dornase alfa alone; although not statistically significant, this was the most common reason for stopping treatment in this arm.
Cough was the most common side effect in the
mannitol alone arm but there was no occurrence of
cough in the
dornase alfa alone arm and the most commonly reported reason of withdrawal from the
mannitol plus
dornase alfa arm was pulmonary exacerbations.
Mannitol (with or without
dornase alfa) was not associated with any increase in isolation of bacteria over the 12-week period.
AUTHORS' CONCLUSIONS: There is evidence to show that treatment with
mannitol over a six-month period is associated with an improvement in some measures of lung function in people with
cystic fibrosis compared to control. There is no evidence that quality of life is improved for participants taking
mannitol compared to control; a decrease in burden of treatment was observed up to four months on
mannitol compared to control but this difference was not maintained to six months. Randomised information regarding the burden of adding
mannitol to an existing treatment is limited. There is no randomised evidence of improvement in lung function or quality of life comparing
mannitol to
dornase alfa alone and to
mannitol plus
dornase alfa.Mannitol as a single or concomitant treatment to
dornase alfa may be of benefit to people with
cystic fibrosis, but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term.The clinical implications from this review suggest that
mannitol could be considered as a treatment in
cystic fibrosis; however, studies comparing its efficacy against other (established)
mucolytic therapies need to be undertaken before it can be considered for mainstream practice.