Therapeutic efficacy of α-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry

Robert A Stockley, David G Parr, Eeva Piitulainen, Jan Stolk, Berend C Stoel, Asger Dirksen, Robert A Stockley, David G Parr, Eeva Piitulainen, Jan Stolk, Berend C Stoel, Asger Dirksen

Abstract

Background: Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry.

Methods: Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15th percentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin® or Prolastin®], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model.

Results: Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively.

Conclusions: The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.

Trial registration: The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.

Figures

Figure 1
Figure 1
Patient disposition by treatment (patients providing CT data). AAT: alpha-1 antitrypsin; EXACTLE: Exacerbations and Computed Tomography scan as Lung Endpoints.
Figure 2
Figure 2
Measurement of progression of emphysema.
Figure 3
Figure 3
Progression of emphysema in AAT-treated versus placebo-treated subjects (modified ITT). *Estimated treatment difference between mean changes in unadjusted 15th percentile lung density from baseline. AAT: alpha-1 antitrypsin; LS: least squares; PD15: 15th percentile lung density.

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