Implementation of a stepped anti-inflammatory reliever therapy intervention with budesonide-formoterol 160/4·5 mcg by Turbuhaler versus usual care for adults presenting during exacerbations of obstructive lung disease suggestive of asthma or chronic obstructive pulmonary disease in a resource-limited setting: an open-label, cluster randomised trial.

Background: In resource-limited countries, chronic respiratory disease is common, and access to diagnosis and to the multiple medications in asthma and chronic obstructive pulmonary disease guidelines is limited. Building on a previous pilot study, we hypothesised that implementation of a simple stepped anti-inflammatory reliever (AIR) approach with budesonide-formoterol in patients presenting with obstructive airways disease and recurrent exacerbations in resource-limited settings would reduce exacerbations compared to usual care. Methods: We conducted a 52-week open-label, cluster randomised controlled trial among adults presenting with recurrent acute respiratory symptoms in Vietnam. 40 district health facilities were assigned to usual care or intervention, which comprised budesonide-formoterol 160/4·5 mcg Turbuhaler: Step 1, one inhalation as-needed for symptoms; Step 2, one inhalation twice-daily plus one inhalation as-needed; Step 3, referral for higher-level care. This was accompanied by quarterly clinical review. Primary outcome was the proportion of participants with at least one moderate or severe exacerbation over 12-months. Secondary outcomes included respiratory hospitalisations, grade 3-4 adverse events, and all-cause mortality. The trial was registered on ANZCTR.org.au (identifier ACTRN12620000649910). Findings: Analysis included 3095 participants recruited between 21 July 2020 and 11 January 2022 (control:1421 vs. intervention: 1674; 75·4% [2334/3095] males; median age 63 years [IQR 55-70]). For the primary outcome, 36·0% (511/1421) control participants had at least one exacerbation during follow-up compared to 28·6% (478/1674) intervention participants (relative risk (RR) 0·794; 95% CI 0·649-0·971; p = 0·03); there was no significant interaction with baseline blood eosinophil count (β = -0·133; 95% CI -0·343 to 0·076; p = 0·21). For the secondary outcomes, fewer participants were hospitalised in the intervention group (control: 24·1% [342/1421] vs. intervention: 17·4% [292/1674]; RR 0·737, 95% CI 0·544-0·998; p = 0·05), and all-cause mortality was similar between groups (control: 3·7% [53/1421] vs. intervention: 3·4% [57/1674]; RR 0·887, 95% CI 0·548-1·435; p = 0·62). There was no significant difference in grade 3-4 adverse events (control: 6·3% [90/1421] vs. intervention: 6·4% [107/1674]; RR 1·004, 95% CI 0·747-1·349). Pneumonia risk was similar (control: 0·8% [11/1421] vs. intervention: 0·4% [7/1674]; RR 0·417, 95% CI 0·135-1·286). Interpretation: Among participants presenting with recurrent exacerbations of undifferentiated chronic respiratory disease, a stepped anti-inflammatory reliever approach was associated with fewer exacerbations and hospitalisations than usual care. This approach may represent a feasible population-level strategy to reduce the global burden of chronic respiratory disease. Funding: This trial was funded by the National Health and Medical Research Council of Australia. The study sponsor was the Woolcock Institute of Medical Research. Budesonide-formoterol was provided by AstraZeneca.