Abstract: We identified and included 22 RCTs randomly assigning 8641 people with COPD to either once-daily LABA/LAMA FDC (6252 participants) or placebo (3819 participants); nine studies had a cross-over design. Studies had a duration of between three and 52 weeks (median 12 weeks). The mean age of participants across the included studies ranged from 59 to 65 years and in 21 of 22 studies, participants had GOLD stage II or III COPD. Concomitant inhaled corticosteroid (ICS) use was permitted in all of the included studies (where stated); across the included studies, between 28% to 58% of participants were using ICS at baseline. Six studies evaluated the once-daily combination of IND/GLY (110/50 μg), seven studies evaluated TIO/OLO (2.5/5 or 5/5 μg), eight studies evaluated UMEC/VI (62.5/5, 125/25 or 500/25 μg) and one study evaluated ACD/FOR (200/6, 200/12 or 200/18 μg); all LABA/LAMA combinations were compared with placebo. The risk of bias was generally considered to be low or unknown (insufficient detail provided), with only one study per domain considered to have a high risk of bias except for the domain 'other bias' which was determined to be at high risk of bias in four studies (in three studies, disease severity was greater at baseline in participants receiving LABA/LAMA compared with participants receiving placebo, which would be expected to shift the treatment effect in favour of placebo). Compared to the placebo, the pooled results for the primary outcomes for the once-daily LABA/LAMA arm were as follows: all-cause mortality, OR 1.88 (95% CI 0.81 to 4.36, low-certainty evidence); all-cause serious adverse events (SAEs), OR 1.06 (95% CI 0.88 to 1.28, high-certainty evidence); acute exacerbations of COPD (AECOPD), OR 0.53 (95% CI 0.36 to 0.78, moderate-certainty evidence); adjusted St George's Respiratory Questionnaire (SGRQ) score, MD -4.08 (95% CI -4.80 to -3.36, high-certainty evidence); proportion of SGRQ responders, OR 1.75 (95% CI 1.54 to 1.99). Compared with placebo, the pooled results for the secondary outcomes for the once-daily LABA/LAMA arm were as follows: adjusted trough forced expiratory volume in one second (FEV1), MD 0.20 L (95% CI 0.19 to 0.21, moderate-certainty evidence); adjusted peak FEV1, MD 0.31 L (95% CI 0.29 to 0.32, moderate-certainty evidence); and all-cause AEs, OR 0.95 (95% CI 0.86 to 1.04; high-certainty evidence). No studies reported data for the 6-minute walk test. The results were generally consistent across subgroups for different LABA/LAMA combinations and doses. Compared with placebo, once-daily LABA/LAMA (either IND/GLY, UMEC/VI or TIO/OLO) via a combination inhaler is associated with a clinically significant improvement in lung function and health-related quality of life in patients with mild-to-moderate COPD; UMEC/VI appears to reduce the rate of exacerbations in this population. These conclusions are supported by moderate or high certainty evidence based on studies with an observation period of up to one year.

Plain-language summary: Twenty-two studies (including 8641 people with COPD) compared once-daily LABA/LAMA in a single inhaler with a dummy inhaler. People were allowed to continue to use their inhaled corticosteroids (ICS) during the studies; approximately a third to a half of people were using their ICS at the beginning of each study. The evidence presented in this review is current up to December 2018. The majority of people who took part in the studies had mild-to-moderate COPD and the average age of people in each study ranged from 59 to 65 years. Six studies evaluated the once-daily combination of indacaterol/glycopyrronium, seven studies evaluated tiotropium/olodaterol, eight studies evaluated umeclidinium/vilanterol and one study evaluated aclidinium/formoterol. People who took once-daily LABA/LAMA using a single inhaler showed a greater improvement in quality of life than those taking placebo in a dummy inhaler; lung function was also improved in people taking once-daily LABA/LAMA. People taking umeclidinium/vilanterol had fewer flare-ups (exacerbations). There was no significant difference between groups (LABA/LAMA versus placebo) in the number of people who died, or in the number of people who experienced serious adverse events or any adverse event. The results were similar for the different LABA/LAMA combinations and doses that we evaluated. The included studies were generally well designed and well reported. People in the studies and those performing the research did not know which treatment people were receiving, which ensures a fair evaluation of the treatments. In three of the studies, people who were taking once-daily LABA/LAMA had more severe COPD at the start of the study than people taking dummy inhalers; this could have reduced the treatment effect seen with LABA/LAMA in these studies so we can be confident that our findings do not overestimate the effect seen with once-daily LABA/LAMA. One of the outcomes of interest (how far a person is able to walk in six minutes) was not reported by any of the included studies. Overall, we can be confident in the conclusions of this review.