Elsevier

The Lancet

Volume 386, Issue 9991, 25–31 July 2015, Pages 360-368
The Lancet

Articles
Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(15)60860-1Get rights and content

Summary

Background

The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure.

Methods

The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18–65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 μM) with a forced expiratory volume in 1 s of 35–70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007).

Findings

Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI −1·50 g/L per year [SE 0·22]; placebo −2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI −0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (−1·45 g/L per year [SE 0·23]) than in the placebo group (−2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06–1·42], p=0·03), but was not at FRC alone (A1PI −1·54 g/L per year [0·24]; placebo −2·02 g/L per year [0·26]; difference 0·48 g/L per year [–0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer).

Interpretation

Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency.

Funding

CSL Behring.

Introduction

Severe deficiency of α1 antitrypsin, first described by Laurell and Eriksson1 in 1963, is associated with a strong tendency for development of emphysema, often, but not always, panlobular in character and basal in distribution. This emphysema is thought to be the result of inadequate neutralisation of naturally occurring proteases, such as neutrophil elastase, by α1 proteinase inhibitor (A1PI), which normally serves as a protease inhibitor.2 A1PI, purified from pooled human plasma and given as an intravenous infusion once a week at a dose of 60 mg/kg, increases and maintains A1PI serum concentrations at more than the accepted protective threshold of 11 μM while producing measurable increases in the antielastase activity of the epithelial lining fluid of the lung.3

No randomised, placebo-controlled clinical trial has been able to substantiate that progression of emphysema is slowed by A1PI augmentation treatment as shown by established disease variables such as forced expiratory volume in 1 s (FEV1). Such trials were not regarded as feasible when augmentation treatment was first developed.4, 5 Changes in FEV1 take place slowly for many years, even in a rapidly progressive disease setting, so that several hundred patients would need to be randomised to augmentation treatment or placebo for 5 years to establish the effect of augmentation treatment on emphysema.4, 5 In a rare disease setting, to do such a trial was not thought possible on the basis of several considerations—not just the absence of a sufficiently large population of identified patients available for study, but also the high costs of such a study and ethical concerns raised by extended treatment with placebo. Since the introduction of augmentation treatment for clinical use in the USA, Germany, Canada, and other nations, findings from observational and cohort studies have shown that the rate of FEV1 loss is slower in individuals who receive augmentation treatment than in those who do not.6, 7, 8 The largest of these observational studies, the National Institutes of Health registry study,9 showed that augmentation treatment was associated with reduced mortality in the most severely obstructed patients. However, such non-randomised findings can be confounded by other factors, such as differences in socioeconomic status and health-care-seeking behaviour between groups.

Investigators have sought more sensitive treatment endpoints than FEV1 that would make possible a definitive randomised, placebo-controlled trial in fewer patients for less time. One such outcome measure is lung density as quantified by CT. In the setting of emphysema related to α1 antitrypsin deficiency, CT lung density seems to better show lung destruction and thus disease severity than do traditional measurements of lung function. CT lung density, for example, is a better predictor of mortality in α1 antitrypsin deficiency emphysema than FEV1 is.10 In 1999, Dirksen and colleagues11 examined both FEV1 and CT lung density endpoints in a randomised, placebo-controlled trial of augmentation treatment, reporting slower rates of lung density loss in patients given augmentation treatment than in those given placebo, although the difference was not significant. In a pilot study of new CT methods, Dirksen and colleagues12 reported similar findings. Although the data from these two trials have been pooled to show a highly significant preservation of lung density with augmentation treatment,13 no single, randomised, placebo-controlled trial has been definitive with respect to this endpoint. For this reason, we undertook the RAPID trial to assess the effect on CT lung density of intravenous A1PI augmentation treatment compared with intravenous placebo in patients with emphysema secondary to severe deficiency of α1 antitrypsin.

Section snippets

Patients and study design

In this multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, we recruited men and women aged 18–65 years with emphysema secondary to α1 antitrypsin deficiency (with a serum A1PI concentration of ≤11 μM) and an FEV1 of 35–70% of the predicted normal value from 28 study centres in 13 countries. We excluded potential participants if they had smoked tobacco within 6 months before recruitment; had undergone or were on the waiting list to undergo lung transplantation,

Results

Between March 1, 2006, and Nov 3, 2010, we screened 208 patients, randomly assigning 180 to active treatment (93 [52%] patients) or placebo (87 [48%] patients), completing data collection on Sept 26, 2012 (figure 1, table 1). Of these 180 patients, 168 (93%) were ZZ genotype; the remainder were other variants with α1 antitrypsin serum concentrations of less than 11 μM. 16 (9%) patients had previously received augmentation treatment, but none within 3 months before randomisation. Assessable lung

Discussion

Although the primary statistical endpoint of PD15 lung density at TLC and FRC combined was non-significant (along with the primary endpoint of FRC alone), this finding can be accounted for by the fact that measurement error for unadjusted PD15 is highest for CT scans obtained at lowest lung volumes (eg, FRC) and lowest for those acquired at highest volumes (eg, TLC).16 The combination of CT data obtained at TLC and FRC results in a measurement error intermediate to that at either TLC alone or

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