A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy

  • Dirksen A
  • Dijkman J
  • Madsen F
 et al. 
  • 52

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Abstract

We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(1)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(1)-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(1)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(1) between 30% and 80% of predicted) participated in a double-blind trial of alpha(1)-antitrypsin augmentation therapy. The patients were randomized to either alpha(1)-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 FEV(1) 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 alpha(1)-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 FEV(1) 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.

Author-supplied keywords

  • Double-Blind Method
  • Female
  • Forced Expiratory Volume
  • Humans
  • Lung/radiography
  • Male
  • Middle Aged
  • Phenotype
  • Pulmonary Diffusing Capacity
  • Pulmonary Emphysema/*drug therapy/etiology/physiop
  • Spirometry
  • Tomography, X-Ray Computed
  • Vital Capacity
  • alpha 1-Antitrypsin Deficiency/complications/drug
  • alpha 1-Antitrypsin/*therapeutic use

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Authors

  • A Dirksen

  • J H Dijkman

  • F Madsen

  • B Stoel

  • D C Hutchison

  • C S Ulrik

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