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Am. J. Respir. Crit. Care Med., Volume 161, Number 3, March 2000, 796-801

Feasibility of a Clinical Trial of Augmentation Therapy for alpha 1-Antitrypsin Deficiency

MARK D. SCHLUCHTER, JAMES K. STOLLER, ALAN F. BARKER, A. SONIA BUIST, RONALD G. CRYSTAL, JAMES F. DONOHUE, ROBERT J. FALLAT, GERARD M. TURINO, CAROL E. VREIM, and MARGARET C. WU, for The Alpha 1-Antitrypsin Deficiency Registry Study Group

Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Pulmonary and Critical Care Medicine, Oregon Health Sciences University, Portland, Oregon; Division of Pulmonary and Critical Care Medicine, The New York Hospital/Cornell University, New York, New York; Pulmonary Division, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; Pulmonary Division, California Pacific Medical Center, San Francisco, California; Department of Medicine, Columbia University, New York, New York; and Division of Lung Diseases and Biostatistics Research Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

We examined the feasibility of a randomized clinical trial of intravenous augmentation therapy for individuals with alpha 1-antitrypsin (alpha 1AT) deficiency, basing calculations on newly available data obtained from the NHLBI Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin. Using rate of FEV1 decline as the primary outcome and adjusting for noncompliance, a study of subjects with Stage II chronic obstructive pulmonary disease (COPD) (initial FEV1 35 to 49% predicted) with biannual spirometry measures obtained over 4 yr of follow-up would require 147 subjects per treatment arm to detect a difference in FEV1 decline of 23 ml/yr (i.e., a 28% reduction), the difference observed in the NHLBI Registry (1-sided test, alpha  = 0.05, 90% power). To detect a 40% reduction in mortality in a 5-year study of subjects with baseline FEV1 35 to 49% predicted, recruited over the first 2 yr and then followed an additional 3 yr, 342 subjects per treatment arm would be needed. Though significant impediments to carrying out a clinical trial exist, including the cost of such a trial and the potential difficulties in recruiting patients for a placebo-controlled trial, we recommend a randomized controlled trial as the best method to evaluate the efficacy of intravenous augmentation therapy and of possible future treatments. Schluchter MD, Stoller JK, Barker AF, Buist AS, Crystal RG, Donohue JF, Fallat RJ, Turino GM, Vreim CE, Wu MC, for the Alpha 1-Antitrypsin Deficiency Registry Study Group. Feasibility of a clinical trial of augmentation therapy for alpha 1-antitrypsin deficiency.




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