A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation

Abstract

Background: We conducted a placebo-controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation.

Methods: We compared azithromycin (250 mg alternate days, 12 weeks) with placebo. Primary outcome was FEV1 change at 12 weeks.

Results: 48 patients were randomised; (25 azithromycin, 23 placebo). It was established, post randomisation that two did not have BOS. 46 patients were analysed as intention to treat (ITT) with 33 'Completers'. ITT analysis included placebo patients treated with open-label azithromycin after study withdrawal.

Outcome: The ITT analysis (n=46, 177 observations) estimated mean difference in FEV1 between treatments (azithromycin minus placebo) was 0.035 L, with a 95% CI of -0.112 L to 0.182 L (p=0.6). Five withdrawals, who were identified at the end of the study as having been randomised to placebo (four with rapid loss in FEV1, one withdrawn consent) had received rescue open-label azithromycin, with improvement in subsequent FEV1 at 12 weeks. Study Completers showed an estimated mean difference in FEV1 between treatment groups (azithromycin minus placebo) of 0.278 L, with 95% CI for the mean difference: 0.170 L to 0.386 L (p=<0.001). Nine of 23 ITT patients in the azithromycin group had ≥10% gain in FEV1 from baseline. No patients in the placebo group had ≥10% gain in FEV1 from baseline while on placebo (p=0.002). Seven serious adverse events, three azithromycin, four in the placebo group, were deemed unrelated to study medication.

Conclusions: Azithromycin therapy improves FEV1 in patients with BOS and appears superior to placebo. This study strengthens evidence for clinical practice of initiating azithromycin therapy in BOS.

Trial registration number: EU-CTR, 2006-000485-36/GB.

Keywords: Lung Transplantation.

Figure 1

CONSORT flow chart summarising the progress of patients through the trial. BOS, bronchiolitis obliterans syndrome; ITT, intention-to-treat.

Figure 2

(A) FEV₁ measurements as a two-panel spaghetti plot of FEV₁ over time in the study. The thickened lines denote FEV₁ from the time a patient withdrew or was withdrawn from study medication. FEV1.0 versus days (placebo group; solid squares) and FEV1.0 versus days (azithromycin group; solid circles). (B) Descriptive plot of FEV₁ data for patients treated with placebo who withdrew or were withdrawn from study medication. Symbols, different for each patient (key) denote FEV₁ measurements. ID, anonymised patient identifier. ‘P’ indicates where a patient was being treated with placebo at the time FEV₁ was measured. ‘A’ denotes where a patient was being treated with azithromycin at the time FEV₁ was measured, after withdrawal from study. Patient 48 was withdrawn from study medication following stomach pains and did not receive azithromycin. Patient 51 withdrew consent and was treated with open-label azithromycin. The remaining four patients had ‘rapid fall’ in FEV₁ and were withdrawn and treated with open label azithromycin.

Figure 3

(A) The change in per cent neutrophils in bronchoalveolar lavage (BAL) from baseline to week 12 for the intention-to-treat (ITT) population, by treatment allocation group (n=28/46). Median change denoted by horizontal line. (B) The change in per cent neutrophils in BAL from baseline to week 12 for the Completer population, by treatment allocation group (n=25/33). Median change denoted by horizontal line. (C) The change in per cent neutrophils in baseline to week 12 for patients treated with azithromycin who had <10% gain in FEV₁ (solid circles) and in patients treated with azithromycin who had a >10% gain in FEV₁ (solid squares).