Summary of findings 1. Summary of findings ‐ 400 mg inhaled mannitol compared with 50 mg inhaled mannitol for cystic fibrosis.

400 mg inhaled mannitol compared with 50 mg inhaled mannitol for CF
Patient or population: adults, children and young people with CF Settings: outpatients Intervention: 400 mg inhaled mannitol Comparison: 50 mg (sub‐therapeutic) inhaled mannitol
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	50 mg inhaled mannitol	400 mg inhaled mannitol
HRQoL ‐ all domains (change from baseline) Scale: age‐appropriate versions of the CFQ‐R questionnaire Follow‐up: up to 6 months	There were no consistent statistically significant differences between treatment groups in changes from baseline for any domains of the CFQ‐R at any of the time points for which data were available.		NA	324 ‐ 507 participants (variable by domains) 2 studies	⊕⊕⊝⊝ low1,2
Lung function: FEV1 mL (change from baseline) Follow‐up: up to 6 months, repeated measures	The mean change from baseline in FEV1 mL ranged across the 50 mg mannitol groups from 26.0 to 32.5.	The mean change from baseline in FEV1 mL in the 400 mg mannitol groups was on average 86.5 higher (95% CI 45.2 to 127.9 higher).	NA	600 participants 2 studies	⊕⊕⊕⊝ moderate1	Data provided by mannitol manufacturer Pharmaxis were analysed via a MMRM analysis.
Lung function: FEV1 % predicted (change from baseline) Follow‐up: up to 6 months, repeated measures	The mean change from baseline in FEV1 % predicted ranged across the 50 mg mannitol groups from 0.62 to 1.63.	The mean change from baseline in FEV1 % predicted in the 400 mg mannitol groups was on average 3.89 higher (95% CI 1.69 to 6.08 higher).	NA	600 participants 2 studies	⊕⊕⊕⊝ moderate1	Data provided by mannitol manufacturer Pharmaxis were analysed via a MMRM analysis.
Lung function: FVC mL (change from baseline) Follow‐up: up to 6 months, repeated measures	The mean change from baseline in FVC mL ranged across the 50 mg mannitol groups from 15.9 to 47.5.	The mean change from baseline in FVC mL in the 400 mg mannitol groups was on average 102.2 higher (95% CI 48.4 to 155.9 higher).	NA	600 participants 2 studies	⊕⊕⊕⊝ moderate1	Data provided by mannitol manufacturer Pharmaxis were analysed via a MMRM analysis.
Lung function: FEF25-75 mL/s (change from baseline) Follow‐up: up to 6 months, repeated measures	The mean change from baseline in FEF25-75 mL/s ranged across the 50 mg mannitol groups from 10.87 to 46.7.	The mean change from baseline in FEF25-75 mL/s in the 400 mg mannitol groups was on average 42.67 higher (95% CI ‐28.07 lower to 113.42 higher).	NA	600 participants 2 studies	⊕⊕⊕⊝ moderate1	Data provided by mannitol manufacturer Pharmaxis were analysed via a MMRM analysis.
Adverse events relating to treatment Scale: mild, moderate, severe and total Follow‐up: up to 6 months	The most commonly adverse events reported were cough and haemoptysis (in 5% and 2% of participants respectively).	The most commonly adverse events reported were cough and haemoptysis (in 10% and 5% of participants respectively).	See comment	600 participants 2 studies	⊕⊕⊕⊝ moderate1	We found no statistically significant differences in rates of adverse events related to treatment (of all severities) between treatment groups.
*For lung function outcomes, the basis for the assumed risk is the range of mean values in the control group and the corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). For Health related Quality of Life and Adverse events, the basis of the assumed risk and the corresponding risk is described in the comments CF: cystic fibrosis;CFQ‐R: Cystic Fibrosis Questionnaire‐Revised version, CI: confidence interval; FEF25-75: mid‐expiratory flow; FEV1: forced expiratory volume at one second; FVC: forced vital capacity; HRQoL: health‐related quality of life; MMRM: mixed model repeated measures; NA: not applicable.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.

1. Evidence downgraded due to indirectness: the participant population included only those with CF who passed the tolerance test and not all potential participants with CF.

2. Evidence downgraded due to indirectness: the CFQ‐R tool used in the studies was not designed to assess mucolytics. Also, pooling of the age‐appropriate tools may not be valid so results should be interpreted with caution.