Abstract: Ten trials met the inclusion criteria with a total of 191 participants. Seven trials evaluated single treatment sessions, one evaluated a two-week intervention, one evaluated a six-week intervention and one a three-month intervention. It is only possible to blind trials of airway clearance and overnight ventilatory support to the outcome assessors. In most of the trials we judged there was an unclear risk of bias with regards to blinding due to inadequate descriptions. The six-week trial was the only one judged to have a low risk of bias for all other domains. One single intervention trial had a low risk of bias for the randomisation procedure with the remaining trials judged to have an unclear risk of bias. Most trials had a low risk of bias with regard to incomplete outcome data and selective reporting. Six trials (151 participants) evaluated non-invasive ventilation for airway clearance compared with an alternative chest physiotherapy method such as the active cycle of breathing techniques or positive expiratory pressure. Three trials used nasal masks, one used a nasal mask or mouthpiece and one trial used a face mask and in one trial it is unclear. Three of the trials reported on one of the review's primary outcome measures (quality of life). Results for the reviews secondary outcomes showed that airway clearance may be easier with non-invasive ventilation and people with cystic fibrosis may prefer it. We were unable to find any evidence that non-invasive ventilation increases sputum expectoration, but it did improve some lung function parameters. Three trials (27 participants) evaluated non-invasive ventilation for overnight ventilatory support compared to oxygen or room air using nasal masks (two trials) and nasal masks or full face masks (one trial). Trials reported on two of the review's primary outcomes (quality of life and symptoms of sleep-disordered breathing). Results for the reviews secondary outcome measures showed that they measured lung function, gas exchange, adherence to treatment and preference, and nocturnal transcutaneous carbon dioxide. Due to the small numbers of participants and statistical issues, there were discrepancies in the results between the RevMan and the original trial analyses. No clear differences were found between non-invasive ventilation compared with oxygen or room air except for exercise performance, which significantly improved with non-invasive ventilation compared to room air over six weeks. One trial (13 participants) evaluated non-invasive ventilation on exercise capacity (interface used was unclear) and did not reported on any of the review's primary outcomes. The trial found no clear differences between non-invasive ventilation compared to no non-invasive ventilation for any of our outcomes. Three trials reported on adverse effects. One trial, evaluating non-invasive ventilation for airway clearance, reported that a participant withdrew at the start of the trial due to pain on respiratory muscle testing. One trial evaluating non-invasive ventilation for overnight support reported that one participant could not tolerate an increase in inspiratory positive airway pressure. A second trial evaluating non-invasive ventilation in this setting reported that one participant did not tolerate the non-invasive ventilation mask, one participant developed a pneumothorax when breathing room air and two participants experienced aerophagia which resolved when inspiratory positive airway pressure was decreased. Non-invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with cystic fibrosis who have difficulty expectorating sputum. Non-invasive ventilation, used in addition to oxygen, may improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate to severe disease. The effect of NIV on exercise is unclear. These benefits of non-invasive ventilation have largely been demonstrated in single treatment sessions with small numbers of participants. The impact of this therapy on pulmonary exacerbations and disease progression remain unclear. There is a need for long-term randomised controlled trials which are adequately powered to determine the clinical effects of non-invasive ventilation in cystic fibrosis airway clearance and exercise.

Plain-language summary: This review includes 10 trials (191 people with cystic fibrosis) - seven single-treatment sessions and a two-week trial, a six-week trial and a three-month trial. Six single-treatment trials, the two-week trial and the three-month trial compared non-invasive ventilation with other airway clearance techniques. Two single-treatment trials and the six-week trial looked at non-invasive ventilation for overnight breathing support compared to oxygen or normal room air. One single-treatment trial compared non-invasive ventilation with no additional treatment during an exercise test. Single-treatment trials of non-invasive ventilation for airway clearance showed that this may be easier with non-invasive ventilation and people with cystic fibrosis may prefer it to other methods. We could not find evidence that non-invasive ventilation increased the amount of mucus coughed up, but it did improve some measures of lung function, at least in the short term. The two-week trial did not demonstrate clear benefits between groups. The original three-month trial report stated an improvement in lung clearance index. One person in one of these trials reported pain on respiratory muscle testing. The three trials comparing overnight support from non-invasive ventilation measured lung function, quality of life and carbon dioxide levels; they showed it is effective, safe and acceptable. We found no clear differences between non-invasive ventilation and oxygen or room air, except for exercise performance which improved with non-invasive ventilation compared to room air after six weeks. Two trials reported side effects. In the first trial, one person found the mask uncomfortable. In the second trial, one person in the room air group had collapsed lungs and two people could not tolerate increased pressure when breathing in. The trial comparing the effects of non-invasive ventilation to no treatment on exercise capacity found no clear differences between groups. Non-invasive ventilation may help alongside other airway clearance techniques, particularly when people with cystic fibrosis have difficulty coughing up mucus and during sleep. Long-term trials are needed with enough people to show the clinical effects of non-invasive ventilation on airway clearance, during sleep and exercise training in severe disease. The benefits of non-invasive ventilation have largely been demonstrated in single-treatment sessions with only small numbers of people. There is limited evidence of some longer-term improvement in lung function in one trial. Our results from the trials of overnight breathing support differed from those in the original analyses, this is likely due to the small numbers of participants and some statistical issues. We judged only the six-week trial to be free from any bias. In the remaining trials, we thought there were low or unclear chances of the results being affected because data were either reported only partially or not at all. We were not sure if the way in which participants were put into the different treatment groups would affect the results of the trials.