Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.

Summary

The current treatment of individuals with alpha-1 antitrypsin deficiency (AATD) who develop lung disease (COPD) is the administration of intravenous purified alpha-1 antitrypsin (augmentation therapy) at a fixed dose of 60 mg/kg per week. This dose aims at increasing the deficient AAT serum levels just above a predetermined "safety threshold" of 11 uM. However, normal levels of AAT are between 25-50 uM. AAT has shown not only to inhibit lung proteases such as neutrophil elastase, but also to modulate inflammation. Given that many subjects with AATD who receive augmentation therapy still have significant lung disease and inflammation, this study will evaluate whether doubling the dose to 120 mg/kg/week has an effect in decreasing lung inflammation. Only the dosing of 60 mg/kg /week has received FDA approval. FDA has granted an IND number to this study to test the higher dose of 120 mg/kg/week. The study will evaluate systemic (serum) and pulmonary (bronchoscopy samples)markers of inflammation in 3 phases: standard dose (4 weeks), double dose (4 weeks) and standard dose (4 weeks).

Timeline

Start

2012-07

Primary completion

2016-05

Completion

2016-05

Publications

• Background Tonelli AR, Brantly ML. Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther Adv Respir Dis. 2010 Oct;4(5):289-312. doi: 10.1177/1753465810373911. Epub 2010 Jul 22.
• Background Stockley RA, Bayley DL, Unsal I, Dowson LJ. The effect of augmentation therapy on bronchial inflammation in alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2002 Jun 1;165(11):1494-8. doi: 10.1164/rccm.2109013.
• Background Petrache I, Hajjar J, Campos M. Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. Biologics. 2009;3:193-204. doi: 10.2147/btt.2009.3088. Epub 2009 Jul 13.
• Campos MA, Geraghty P, Holt G, Mendes E, Newby PR, Ma S, Luna-Diaz LV, Turino GM, Stockley RA. The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy. A Pilot Clinical Trial. Am J Respir Crit Care Med. 2019 Aug 1;200(3):318-326. doi: 10.1164/rccm.201901-0010OC.

Drugs

Indications