Abstract: One quasi-randomised and 19 randomised controlled studies (924 children and adults) were included; 16 studies (n = 639) analysed oral antioxidant supplementation and four analysed inhaled supplements (n = 285). Only one of the 20 included studies was judged to be free of bias. Oral supplements versus control The change from baseline in forced expiratory volume in one second (FEV1) % predicted at three months and six months was only reported for the comparison of NAC to control. Four studies (125 participants) reported at three months; we are uncertain whether NAC improved FEV1 % predicted as the quality of the evidence was very low, mean difference (MD) 2.83% (95% confidence interval (CI) -2.16 to 7.83). However, at six months two studies (109 participants) showed that NAC probably increased FEV1 % predicted from baseline (moderate-quality evidence), MD 4.38% (95% CI 0.89 to 7.87). A study of a combined vitamin and selenium supplement (46 participants) reported a greater change from baseline in FEV1 % predicted in the control group at two months, MD -4.30% (95% CI -5.64 to -2.96). One study (61 participants) found that NAC probably makes little or no difference in the change from baseline in quality of life (QoL) at six months (moderate-quality evidence), standardised mean difference (SMD) -0.03 (95% CI -0.53 to 0.47), but the two-month combined vitamin and selenium study reported a small difference in QoL in favour of the control group, SMD -0.66 (95% CI -1.26 to -0.07). The NAC study reported on the change from baseline in body mass index (BMI) (62 participants) and similarly found that NAC probably made no difference between groups (moderate-quality evidence). One study (69 participants) found that a mixed vitamin and mineral supplement may lead to a slightly lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) provided information on adverse events, but did not find any clear and consistent evidence of differences between treatment or control groups with the quality of the evidence ranging from low to moderate. Studies of β-carotene and vitamin E consistently reported greater plasma levels of the respective antioxidants. Inhaled supplements versus control Two studies (258 participants) showed inhaled glutathione probably improves FEV1 % predicted at three months, MD 3.50% (95% CI 1.38 to 5.62), but not at six months compared to placebo, MD 2.30% (95% CI -0.12 to 4.71) (moderate-quality evidence). The same studies additionally reported an improvement in FEV1 L in the treated group compared to placebo at both three and six months. One study (153 participants) reported inhaled glutathione probably made little or no difference to the change in QoL from baseline, MD 0.80 (95% CI -1.63 to 3.23) (moderate-quality evidence). No study reported on the change from baseline in BMI at six months, but one study (16 participants) reported at two months and a further study (105 participants) at 12 months; neither study found any difference at either time point. One study (153 participants) reported no difference in the time to the first pulmonary exacerbation at six months. Two studies (223 participants) reported treatment may make little or no difference in adverse events (low-quality evidence), a further study (153 participants) reported that the number of serious adverse events were similar across groups. With regards to micronutrients, there does not appear to be a positive treatment effect of antioxidant micronutrients on clinical end-points; however, oral supplementation with glutathione showed some benefit to lung function and nutritional status. Based on the available evidence, inhaled and oral glutathione appear to improve lung function, while oral administration decreases oxidative stress; however, due to the very intensive antibiotic treatment and other concurrent treatments that people with CF take, the beneficial effect of antioxidants remains difficult to assess in those with chronic infection without a very large population sample and a long-term study period. Further studies, especially in very young children, using outcome measures such as lung clearance index and the bronchiectasis scores derived from chest scans, with improved focus on study design variables (such as dose levels and timing), and elucidating clear biological pathways by which oxidative stress is involved in CF, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn. The benefit of antioxidants in people with CF who receive CFTR modulators therapies should also be assessed in the future.

Plain-language summary: We included 20 studies (924 people with CF, almost equal gender split, aged six months to 59 years); 16 studies compared oral supplements to placebo ('dummy' treatment) and four compared inhaled supplements to placebo. Oral supplements We are uncertain whether NAC changes lung function (forced expiratory volume in one second (FEV1) % predicted) at three months (four studies, 125 participants, very low-quality evidence), but at six months two studies (109 participants) reported NAC probably improved FEV1 % predicted (moderate-quality evidence). One study (46 participants) reported a greater change in FEV1 % predicted with placebo than with a combined vitamin and selenium supplement after two months. One study (61 participants) reported little or no difference in quality of life (QoL) scores between NAC and control after six months (moderate-quality evidence), but the two-month combined vitamin and selenium study reported slightly better QoL scores in the control group. NAC probably made no difference to body mass index (BMI) (one study, 62 participants, moderate-quality evidence). One study (69 participants) reported that a mixed vitamin and mineral supplement may lead to a lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) did not find any clear and consistent differences in side effects between groups (evidence ranged from low to moderate quality). Vitamin E and β-carotene studies consistently reported greater levels of these antioxidants in blood samples. Inhaled supplements In two studies (258 participants), inhaled glutathione probably improved FEV1 % predicted compared to placebo at three months but not at six months (moderate-quality evidence); these studies also reported a greater improvement in FEV1 litres with glutathione compared to placebo at both time points. Two studies (258 participants) found little or no difference in the change in QoL scores (moderate-quality evidence). One two-month study (16 participants) and a 12-month study (105 participants) reported no difference between groups in the change in BMI. There was no difference in the time to the first pulmonary exacerbation in one six-month study. Two studies (223 participants) reported no difference between groups in side effects (low-quality evidence) and another study (153 participants) reported that the number of serious side effects were similar across groups. Vitamin and mineral supplements do not seem to improve clinical outcomes. Inhaled glutathione appears to improve lung function, while oral administration lowers oxidative stress, with benefits to lung function and nutritional measures. Intensive antibiotic and other concurrent treatments for people with CF and chronic infection mean it is difficult to assess the effect of antioxidants without a very large and long study. Future research should look at how antioxidants affect people with CF taking CFTR modulator therapies. Evidence ranged from very low to moderate quality. All but one study had some bias; mostly because data were not fully reported (likely to affect our results). We were also largely unsure if participants knew which treatment they received, both in advance and once the studies started (unsure how this might affect our results).