Efficacy and safety of inhaled alpha-1-antitrypsin in patients with severe alpha-1-antitrypsin deficiency and frequent exacerbations of Chronic Obstructive Pulmonary Disease.

Patients with inherited alpha-1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently suffer from exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment. We randomly assigned 168 patients to receive twice daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an eDiary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary end-points included change in the nature of the exacerbation by the Anthonisen criteria. Safety was also assessed. Time to first moderate or severe exacerbation was at median 112 days (IQR 40, 211) for AAT and 140 days (IQR 72, 142) for placebo, p=0·0952. The mean yearly rate of all exacerbations in the AAT and placebo groups was 3.12 and 2.67 (p=0.31), respectively. More patients receiving AAT reported treatment-related TEAEs (Treatment Emergent Adverse Events) compared to placebo (57·5% versus 46·9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, the rate of safety events in the AAT treated group dropped to that of the placebo group. We conclude that in AATD patients with severe COPD and frequent exacerbations AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.