We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, α₁-antitrypsin, can prevent the progression of pulmonary emphysema in patients with α₁-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with α₁-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV₁ between 30% and 80% of predicted) participated in a double-blind trial of α₁-antitrypsin augmentation therapy. The patients were randomized to either α₁-antitrypsin (250 mg/kg) or albumin (625 mg/kg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV₁ between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean ± SEM) was 2.6 ± 0.41 g/L/yr for placebo as compared with 1.5 ± 0.41 g/L/yr for α₁-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV₁ showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr. Dirksen A, Dijkman JH, Madsen F, Stoel B, Hutchison DCS, Ulrik CS, Skovgaard LT, Kok-Jensen A, Rudolphus A, Seersholm N, Vrooman HA, Reiber JHC, Hansen NC, Heckscher T, Viskum K, Stolk J. A randomized clinical trial of α₁-antitrypsin augmentation therapy.