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Meta-Analysis
. 2018 Feb 9;2(2):CD008649.
doi: 10.1002/14651858.CD008649.pub3.

Inhaled mannitol for cystic fibrosis

Sarah J Nevitt  1 , Judith Thornton, Clare S Murray, Tiffany Dwyer
Affiliations
Meta-Analysis

Inhaled mannitol for cystic fibrosis

Sarah J Nevitt et al. Cochrane Database Syst Rev. .

Update in

  • Inhaled mannitol for cystic fibrosis.
    Nevitt SJ, Thornton J, Murray CS, Dwyer T. Nevitt SJ, et al. Cochrane Database Syst Rev. 2020 May 1;5(5):CD008649. doi: 10.1002/14651858.CD008649.pub4. Cochrane Database Syst Rev. 2020. PMID: 32358807 Free PMC article.

Abstract

Background: Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review.

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 methods: 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: 28 September 2017.

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. The quality of the evidence was assessed using GRADE.

Main results: 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).

Authors' conclusions: 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.

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Conflict of interest statement

Sarah Nevitt has no potential conflict of interest to declare.

Dr Murray was local principal investigator (and thus recruiting participants) for an inhaled mannitol study run by Pharmaxis. Her institution was paid on a per‐participant basis for participants recruited to the study, but she herself did not benefit financially for running the study.

Dr Thornton was pharmacist at one site for a clinical study of inhaled mannitol in children and young people with CF in the UK. Dr Thornton’s main employment is with NICE, Centre for Guidelines. NICE Centre for Health Technology Evaluation, have published an appraisal of mannitol in CF. The Centre for Guidelines have published a guideline for the management of CF which includes mannitol. Dr Thornton is also a member of the GRADE working group.

Tiffany Dwyer declares she has worked on a trial of hypertonic saline in people with cystic fibrosis and another trial in non‐cystic fibrosis bronchiectasis. Hypertonic saline is a mucolytic agent that works similarly to inhaled mannitol.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 1 HRQoL ‐ respiratory (change from baseline).
1.2
1.2. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 2 HRQoL ‐ vitality (change from baseline).
1.3
1.3. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 3 HRQoL ‐ physical (change from baseline).
1.4
1.4. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 4 HRQoL ‐ emotion (change from baseline).
1.5
1.5. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 5 HRQoL ‐ eating (change from baseline).
1.6
1.6. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 6 HRQoL ‐ health (change from baseline).
1.7
1.7. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 7 HRQoL ‐ social (change from baseline).
1.8
1.8. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 8 HRQoL ‐ body (change from baseline).
1.9
1.9. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 9 HRQoL ‐ role (change from baseline).
1.10
1.10. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 10 HRQoL ‐ weight (change from baseline).
1.11
1.11. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 11 HRQoL ‐ digestion (change from baseline).
1.12
1.12. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 12 FEV1 ml (repeated measures, change from baseline).
1.13
1.13. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 13 FEV1 % predicted (repeated measures, change from baseline).
1.14
1.14. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 14 FVC mL (repeated measures, change from baseline).
1.15
1.15. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 15 FEF25‐75 mL/s (repeated measures, change from baseline).
1.16
1.16. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 16 Adverse events at up to 6 months(mild).
1.17
1.17. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 17 Adverse events at up to 6 months (moderate).
1.18
1.18. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 18 Adverse events at up to 6 months (severe).
1.19
1.19. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 19 Adverse events at up to 6 months (total).
1.20
1.20. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 20 Participants with treatment‐related respiratory and thoracic adverse events leading to study discontinuation.
1.21
1.21. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 21 Number of patients with protocol defined pulmonary exacerbations.
1.22
1.22. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 22 Time to first protocol defined pulmonary exacerbation (PDPE).
1.23
1.23. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 23 Number of patients needing additional antibiotics.
1.24
1.24. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 24 Number of participants requiring hospitalisation.
1.25
1.25. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 25 Duration of hospitalisation.
1.26
1.26. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 26 Sputum weight (g).
1.27
1.27. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 27 Sputum weight (g) (change from baseline).
1.28
1.28. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 28 Microbiology: pathogens present at end of study.
1.29
1.29. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 29 Burden of treatment (change from baseline).
1.30
1.30. Analysis
Comparison 1 Mannitol versus control ‐ parallel studies of individuals with cystic fibrosis, Outcome 30 Adherence ≥ 60%.
2.1
2.1. Analysis
Comparison 2 Mannitol versus control ‐ cross‐over studies of individuals with cystic fibrosis, Outcome 1 FEV1 % predicted (absolute change from baseline).
2.2
2.2. Analysis
Comparison 2 Mannitol versus control ‐ cross‐over studies of individuals with cystic fibrosis, Outcome 2 FEV1 % predicted (absolute change from baseline ‐ subgroup analysis by age).
2.3
2.3. Analysis
Comparison 2 Mannitol versus control ‐ cross‐over studies of individuals with cystic fibrosis, Outcome 3 FEV1 % predicted (absolute change from baseline ‐ subgroup analysis by dornase alfa use.
2.4
2.4. Analysis
Comparison 2 Mannitol versus control ‐ cross‐over studies of individuals with cystic fibrosis, Outcome 4 FEV1 % predicted (relative change from baseline).
2.5
2.5. Analysis
Comparison 2 Mannitol versus control ‐ cross‐over studies of individuals with cystic fibrosis, Outcome 5 FVC % predicted (absolute change from baseline).
2.6
2.6. Analysis
Comparison 2 Mannitol versus control ‐ cross‐over studies of individuals with cystic fibrosis, Outcome 6 FVC % predicted (relative change from baseline).
2.7
2.7. Analysis
Comparison 2 Mannitol versus control ‐ cross‐over studies of individuals with cystic fibrosis, Outcome 7 FEF25‐75 % predicted (absolute change from baseline).
2.8
2.8. Analysis
Comparison 2 Mannitol versus control ‐ cross‐over studies of individuals with cystic fibrosis, Outcome 8 FEF25‐75 % predicted (relative change from baseline).
2.9
2.9. Analysis
Comparison 2 Mannitol versus control ‐ cross‐over studies of individuals with cystic fibrosis, Outcome 9 Sputum weight (grams) (post‐initial treatment).
3.1
3.1. Analysis
Comparison 3 Mannitol versus control ‐ parallel study of individuals with cystic fibrosis, hospitalised due to pulmonary exacerbations, Outcome 1 HRQoL ‐ change from baseline in CFCS total score.
3.2
3.2. Analysis
Comparison 3 Mannitol versus control ‐ parallel study of individuals with cystic fibrosis, hospitalised due to pulmonary exacerbations, Outcome 2 HRQoL ‐ change from baseline in CFQ‐R respiratory domain.
3.3
3.3. Analysis
Comparison 3 Mannitol versus control ‐ parallel study of individuals with cystic fibrosis, hospitalised due to pulmonary exacerbations, Outcome 3 FEV1 % predicted (change from baseline).
3.4
3.4. Analysis
Comparison 3 Mannitol versus control ‐ parallel study of individuals with cystic fibrosis, hospitalised due to pulmonary exacerbations, Outcome 4 FVC % predicted (change from baseline).
3.5
3.5. Analysis
Comparison 3 Mannitol versus control ‐ parallel study of individuals with cystic fibrosis, hospitalised due to pulmonary exacerbations, Outcome 5 FEF25‐75 % predicted (change from baseline).
4.1
4.1. Analysis
Comparison 4 Mannitol versus dornase alfa ‐ cross‐over study of individuals with cystic fibrosis, Outcome 1 FEV1 (% change from baseline).
4.2
4.2. Analysis
Comparison 4 Mannitol versus dornase alfa ‐ cross‐over study of individuals with cystic fibrosis, Outcome 2 FVC (% change from baseline).
4.3
4.3. Analysis
Comparison 4 Mannitol versus dornase alfa ‐ cross‐over study of individuals with cystic fibrosis, Outcome 3 FEF25‐75 (% change from baseline).
5.1
5.1. Analysis
Comparison 5 Mannitol plus dornase alfa versus dornase alfa ‐ cross‐over study of individuals with cystic fibrosis, Outcome 1 FEV1 (% change from baseline).
5.2
5.2. Analysis
Comparison 5 Mannitol plus dornase alfa versus dornase alfa ‐ cross‐over study of individuals with cystic fibrosis, Outcome 2 FVC (% change from baseline).
5.3
5.3. Analysis
Comparison 5 Mannitol plus dornase alfa versus dornase alfa ‐ cross‐over study of individuals with cystic fibrosis, Outcome 3 FEF25‐75 (% change from baseline).
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