Randomized, Placebo-Controlled Trials in Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a condition caused by the inheritance of two mutated SERPINA1 gene alleles. Individuals with AATD are at increased risk of injury to the liver and lungs. The pulmonary manifestations include precocious onset of pulmonary emphysema and bronchiectasis. For nearly three decades, treatment has been available to individuals with emphysema caused by AATD, but this therapy-augmentation of plasma and tissue alpha-1 antitrypsin levels by intravenous administration of human plasma-derived protein-was approved by regulatory authorities based on its biochemical efficacy. This therapy appears to slow the progression of emphysema in patients with AATD. The medical, patient, and regulatory communities have sought assurance that this expensive therapy provides measurable clinical benefit. Documenting such benefit has been difficult because of the slow progression of the underlying lung disease in AATD, the rarity of this genetic condition, and the lack of direct quantitative measurements of emphysema progression. Over the past decade, quantitative computed tomography (CT) densitometry of the lungs has been found to correlate with severity and progression of emphysema. The recent publication of a well-powered, masked, placebo-controlled study using CT densitometry to evaluate the effectiveness of augmentation therapy at slowing the progression of emphysema has provided some assurance of the clinical efficacy of this therapy.