Abstract: Six studies (reported in 50 publications) were included with a total of 784 participants. Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population. Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole. While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies. Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality. For the comparisons 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. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF. For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. 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. In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa). There is moderate-quality 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 low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa. The clinical implications from this review suggest that mannitol could be considered as a treatment in 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. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.

Plain-language summary: We included six studies (with a total of 784 adults and children) in this review. Five 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 sixth 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 five of the six studies if they were using hypertonic saline. Treatment in these studies lasted from 12 days to six months. Five studies provided the treatments to people as outpatients and in one study, the children treated were in hospital due to pulmonary exacerbations (flare ups of disease). It was difficult to combine evidence from the studies in this review due to differences in the designs of the studies, treatments examined and the settings (hospital or outpatients). Some additional information was obtained from the drug manufacturer and one study author to aid the review. The review found low- to very low-quality evidence that there is no difference between mannitol and control treatments or mannitol given either with or without additional dornase alfa in terms of quality of life. There was moderate-quality evidence of improvements in some measures of lung function across the larger studies comparing mannitol to control. Beneficial effects were also seen in the subgroup of adults and in both those who were using dornase alfa and those who were not. Cough (including coughing up blood), contraction of the airways, pain in the pharynx or larynx and post-treatment vomiting were the most commonly reported side effects on both treatments, but there was no evidence to suggest that these side effects occurred more on mannitol than on control treatments or on dornase alfa. 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. 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 everyone taking part 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 people who dropped out of the studies might affect how the results are interpreted, as well as how many people were recruited into the studies and how they were selected from all people with cystic fibrosis who could have been included. 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 people 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.