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