Mannitol, an inhaled drug, for treating lung disease in cystic fibrosis

Review question

We reviewed the evidence about the effect of inhaling mannitol to treat lung disease in people with cystic fibrosis.

Background

Cystic fibrosis is a genetic disorder that affects the exocrine glands (sweat glands and others). Lung infections produce thick mucus (phlegm) which can block air passages and cause more infection and repeated inflammation. In turn, this progressively damages the lungs and can eventually cause respiratory failure. There are several drugs that are used to clear mucus from the airways of people with cystic fibrosis and inhaled dry powder mannitol is a new one that may improve their lung function. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which are delivered by a nebuliser (e.g. hypertonic saline).

Search date

The evidence is current to: 16 April 2015.

Study characteristics

We included four studies in this review with a total of 667 volunteers. Three of these studies compared a standard dose of mannitol with control (a very low dose of mannitol or a version of mannitol which did not allow the active drug to reach the lungs) and the fourth study compared mannitol with nebulised recombinant human deoxyribonuclease (dornase alfa), both alone and taken together. Participants could continue using dornase alfa and other standard therapies, but were excluded from the studies if they were using hypertonic saline. Treatment in these studies lasted from two weeks to six months and included both adults and children.

Key results

The results were not easily comparable, but some additional information was obtained from the drug manufacturer and one study author to aid the review. The review found little evidence that mannitol significantly improves quality of life when compared with control in three studies or in a study looking at mannitol given either with or without additional dornase alfa. There were improvements in some measures of lung function across the studies comparing mannitol to control. Beneficial effects were also seen in the subgroup of adults and in both volunteers who were using dornase alfa or who were not.

Treatment with mannitol led to a drop in the number of flare ups of disease (as defined in the studies), on average we estimate mannitol led to a 29% reduction, although the actual reduction could vary from 2% to 49%. None of the studies compared mannitol to nebulised hypertonic saline and so we can not comment on which agent is better for airway clearance. More research is needed to answer this question. Mannitol was not linked to any increase in the isolation of bacteria over a six-month period, this is reassuring as many organisms are able to use mannitol to grow.

Quality of the evidence

We judged the quality of the evidence from this review to be of very low to moderate quality, depending on the outcome measured. We do not think that the way the studies were designed affected the results. We judged that all volunteers had equal chances of being in either of the treatment groups and would not have known in advance or during the study which treatment they were receiving. However, the numbers of volunteers who dropped out of the studies might affect how the results are interpreted. Although some of these issues were resolved when the drug's manufacturer, who also sponsored the studies, provided some additional information. It is important to realise that before volunteers started the study, they took a test to see if they could tolerate mannitol and only those who did could carry on. This means that the results of the studies only apply to those people with cystic fibrosis who can tolerate mannitol.

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.

Read the full abstract...
Background: 

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: 

To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment.

Search strategy: 

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences.

Date of last search: 16 April 2015.

Selection criteria: 

All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment.

Data collection and analysis: 

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.

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