Feasibility of a Clinical Trial of Augmentation Therapy for α₁-Antitrypsin Deficiency

Abstract

We examined the feasibility of a randomized clinical trial of intravenous augmentation therapy for individuals with alpha 1-antitrypsin (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 FEV 1 decline as the primary outcome and adjusting for noncompliance, a study of subjects with Stage II chronic obstructive pulmonary disease (COPD) (initial FEV 1 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 FEV 1 decline of 23 ml/yr (i.e., a 28% reduction), the difference observed in the NHLBI Registry (1-sided test, 0.05, 90% power). To detect a 40% reduction in mortality in a 5-year study of subjects with baseline FEV 1 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 1-antitrypsin deficiency .

Outcomes for COPD pharmacological trials: from lung function to biomarkers

“…DL,CO has also been used in studies evaluating the effects of lung volume reduction surgery [74,75], rehabilitation [73] and therapy for a 1 -antitrypsin deficiency [81,82]. However, it is a measure that can only be performed in stable conditions rather than during exacerbations of COPD.…”

Exploring the role of CT densitometry: a randomised study of augmentation therapy in 1-antitrypsin deficiency

“…A randomised placebo-controlled trial of a 1 -AT augmentation therapy with traditional physiological measures used as the primary end-point has not been undertaken because such a study is considered impractical [2,3]; this therapy is therefore currently justified by clinical logic, proven biochemical efficacy [4] and data from well-controlled observational studies that are suggestive of treatment efficacy [5][6][7][8]. Forced expiratory volume in 1 s (FEV1) has been regarded as the ''gold standard'' outcome measure as a surrogate marker for emphysema progression; however, in order to detect a difference in FEV1 decline of 15 mL?yr -1 , it has been estimated that 494 subjects with a baseline FEV1 of 35-79% predicted would be required per treatment arm over 3 yrs [2].…”

Report of a workshop: quantitative computed tomography scanning in longitudinal studies of emphysema

“…SCHLUCHTER et al [2] made power estimates from data of the National Heart Lung and Blood Institute Registry of patients with severe deficiency of a 1 -AT. Using subjects with initial FEV1 35-49% predicted, biannual spirometry obtained over 4 yrs and adjustment for noncompliance would require 147 subjects per treatment arm to detect a difference in FEV1 decline of 23 mL?yr -1 or a 28% reduction in rate of decline.…”