Alpha-1-antitrypsin replacement therapy: will its efficacy ever be proved?

The study concerned with the treatment of alpha-1antitrypsin (AT) deficiency, which appears in this issue of the Journal [1], requires that we all give serious thought to this controversial and difficult topic. Before dealing directly with the issues raised by the design of this study, however, it is necessary to give some account of the events that led up to it. AT deficiency is a hereditary disorder that can lead to the development of disabling pulmonary emphysema at a relatively early age. AT is the main serum inhibitor of proteolytic enzymes and one of its most important functions is thought to be the inactivation of the potent elastase produced by polymorphonuclear leucocytes. In the severe form of the deficiency (subjects homozygous for Pi type Z) the serum AT concentration may be no more than 10–20% of normal and in these circumstances the pulmonary elastic tissue may be degraded by the unopposed action of the leucocyte elastase. Cigarette smoking can seriously exacerbate this effect. The disability and early mortality that can result from this disorder make it entirely logical to attempt replacement of the missing serum protein fraction and potentially suitable therapy has been available for some years [2]. The current commercial products require intravenous administration and have a half-life of no more than 5 days. In addition, such treatment might have to be administered for many years and perhaps for the lifetime of the patient. There has been extensive debate on how this therapy should be evaluated and in particular whether a randomized controlled trial should be performed. The problems of such a trial were recognized to be substantial; emphysema usually evolves slowly over a period of many years and any trial requiring serial evaluation of lung function would need to continue for a corresponding period of time. The possibility of conducting a randomized controlled trial was discussed by a workshop supported by the USA National Heart, Lung and Blood Institute (NHLBI) [3]. Pilot studies had already shown that, in patients with severe deficiency, the serum AT concentration could be raised from a mean of 37 mg·dL-1 to 108 mg·dL-1 by intravenous infusion of 4 g of AT replacement [2, 4]. The members of the Workshop considered that the optimal form of trial would be one carried out in patients with relatively mild disease and that this would require measurement of the decline in forced expiratory volume in one second (FEV1) in treated and untreated groups over a period of some years. At that time, there was no data on the natural rate of decline in lung function in AT deficient patients and the authors, while recognizing the possible errors of this approach, were obliged to base their estimates of sample size on values obtained in cases of non-AT deficient chronic obstructive pulmonary disease (COPD) from previous studies. They came to the conclusion that a total of over 300 patients would be needed to show a 50% reduction in the rate of decline in FEV1, in a study lasting for 5 yrs. In a series of AT deficient cases published a few years later [5], 60 cases homozygous for Pi type Z, who had been followed up for some years, were identified; their mean rate of decline in FEV1 was 93 mL·yr-1 with a large standard deviation (143 mL·yr-1), as is often found in this type of survey. The authors concluded again that large numbers would be required, 253 in both treated and untreated groups in order to detect a 40% reduction in the rate of decline in FEV1 in a study lasting 3 yrs. It was pointed out that, nevertheless, this would be far preferable to a mortality study where much more severely affected patients would be involved and the numbers required would be even greater. The production of AT replacement therapy on a commercial scale was developed by Cutter Biological, Miles Inc. (subsequently Bayer AG, Leverkusen, Germany) [6] and by the Centre Régional de Transfusion Sanguine (Lille, France) [7]; the commercial forms of AT have similar activity to the native protein. Pasteurization was shown to bring about rapid inactivation of retroviruses including human immunodeficiency virus (HIV) [8] and the serum AT levels in deficient subjects could be raised to normal without serious adverse reactions [9, 10]. Alongside the development of commercial AT replacement therapy, a number of studies of the natural history of the disease in several countries appeared in the literature [5, 11–13]. The average rates of decline in FEV1 were of the same order in the majority of studies but there were wide variations among patients, as demonstrated by the large standard deviations. Further calculations suggested that the required number of patients was perhaps not so great as previously envisaged and could be achieved by a multinational European study [14]; a parallel group study was recommended with patients randomized to treatment and nontreatment groups, ideally on a double-blind basis, the patients having FEV1 ranging 35–75% of the reference value, with EDITORIAL