Intravenous Alpha-1 Antitrypsin for Hospitalized Patients With COPD Exacerbations (AECOPD Study)

Summary

Intravenous augmentation therapy with purified preparations of AAT (Alpha1-antitrypsin) derived from human plasma is a well consolidated specific therapeutic option to treat the severe deficient state of AAT. Prolastin is used to restore the balance between AAT and elastases in the lung and consequently to prevent a further deterioration in the pulmonary emphysema. Recently, in patients with COVID-19, without genetically lowered AAT levels with moderate to severe ARDS, treatment with AAT was demonstrated to be safe, feasible, and biochemically efficacious as an anti-inflammatory therapeutic therapy. The aim of the study, based on biological plausibility, is to evaluate the safety and efficacy (from a biological perspective) of the administration of intravenous plasma-purified AAT as an anti-inflammatory treatment for patients admitted to hospital because of a COPD exacerbation leading to an acute or an acute on chronic respiratory failure. Thirty-six adult patients hospitalized because of a COPD exacerbation leading to an acute or an acute on chronic respiratory failure will be enrolled by the two sites involved in the study, the Pneumology Unit of Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) and the Pneumology Unit of IRCCS Istituto Clinico Humanitas, Rozzano (Milano, Italy). Participants will be randomized 2:1 in the active treatment group (standard treatment + IV administration of Prolastin) or in the placebo group (standard treatment+ IV administration of 0.9% sodium chloride). To address the clinical question from a biological perspective, we will investigate the decrease in inflammatory markers in the active treated group in comparison with the placebo group. The primary objective is to demonstrate a significant reduction in systemic inflammation by IV Prolastin administered once at 120 mg per kilogram of body weight in patients with moderate to severe AECOPD, as assessed by the change in plasma concentration of IL6 at 7 days after randomization, in the active treatment group with respect to placebo group. Secondary outcomes are: 1. Difference in change in plasma concentration of IL-1b, IL-5, IL-8, IL-10, and soluble TNF receptor 1 (sTNFR1), CRP at 7 days after randomization. 2. Differences in AAT antielastase activity, the amount of active elastase, the AAT levels in serum at baseline and at 7 days after randomization. 3. Difference in treatment failure rate. Treatment failure is a composite endpoint of need for either NIV or CPAP or need of ETI or need of transfer to ICU or in-hospital death after randomization 4. Impact of AECOPD on overall health, daily life, and perceived well-being in patients with obstructive airways disease by the change of St. George's Respiratory Questionnaire (SGRQ) score from Day 7 to follow-up (30 days after hospital discharge). 5. Differences in type and number of AEs and SAEs in the two groups The expected duration of subject participation is from randomization to 30 days after hospital discharge, with a follow up phone contact.

Timeline

Start

2025-10-01

Primary completion

2027-10-07

Completion

2027-12-01

Publications

• Results Celli BR, Fabbri LM, Aaron SD, Agusti A, Brook R, Criner GJ, Franssen FME, Humbert M, Hurst JR, O'Donnell D, Pantoni L, Papi A, Rodriguez-Roisin R, Sethi S, Torres A, Vogelmeier CF, Wedzicha JA. An Updated Definition and Severity Classification of Chronic Obstructive Pulmonary Disease Exacerbations: The Rome Proposal. Am J Respir Crit Care Med. 2021 Dec 1;204(11):1251-1258. doi: 10.1164/rccm.202108-1819PP. No abstract available.
• Results Bristow CL. Measuring the Concentration of Active Alpha-1 Antitrypsin in Serum. Methods Mol Biol. 2024;2750:71-77. doi: 10.1007/978-1-0716-3605-3_7.
• Results Lee MC, Wu WY, Lu HY, Hsieh HN, Wu WH. Conducting the non-inferiority test for the means with unknown coefficient of variation in a three-arm trial. BMC Med Res Methodol. 2023 Aug 11;23(1):183. doi: 10.1186/s12874-023-01990-w.
• Results Escribano Duenas AM, Martin Garcia M, Tortajada Goitia B, Arenas Villafranca JJ. Case report: Self-administration of alpha-1 antitrypsin therapy: a report of two cases. Front Pharmacol. 2023 Nov 21;14:1291677. doi: 10.3389/fphar.2023.1291677. eCollection 2023.
• Results Blanco I, Lara B, de Serres F. Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema. Orphanet J Rare Dis. 2011 Apr 12;6:14. doi: 10.1186/1750-1172-6-14.
• Results Wencker M, Banik N, Buhl R, Seidel R, Konietzko N. Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha1-AT-study group. Eur Respir J. 1998 Feb;11(2):428-33. doi: 10.1183/09031936.98.11020428.
• Results Stoller JK, Fallat R, Schluchter MD, O'Brien RG, Connor JT, Gross N, O'Neil K, Sandhaus R, Crystal RG. Augmentation therapy with alpha1-antitrypsin: patterns of use and adverse events. Chest. 2003 May;123(5):1425-34. doi: 10.1378/chest.123.5.1425.
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• Results Greulich T, Chlumsky J, Wencker M, Vit O, Fries M, Chung T, Shebl A, Vogelmeier C, Chapman KR, McElvaney NG; RAPID Trial Group. Safety of biweekly alpha1-antitrypsin treatment in the RAPID programme. Eur Respir J. 2018 Nov 29;52(5):1800897. doi: 10.1183/13993003.00897-2018. Print 2018 Nov.
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• Results McElvaney NG, Burdon J, Holmes M, Glanville A, Wark PA, Thompson PJ, Hernandez P, Chlumsky J, Teschler H, Ficker JH, Seersholm N, Altraja A, Makitaro R, Chorostowska-Wynimko J, Sanak M, Stoicescu PI, Piitulainen E, Vit O, Wencker M, Tortorici MA, Fries M, Edelman JM, Chapman KR; RAPID Extension Trial Group. Long-term efficacy and safety of alpha1 proteinase inhibitor treatment for emphysema caused by severe alpha1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet Respir Med. 2017 Jan;5(1):51-60. doi: 10.1016/S2213-2600(16)30430-1. Epub 2016 Dec 2.
• Results 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.
• Results McElvaney OJ, McEvoy NL, Boland F, McElvaney OF, Hogan G, Donnelly K, Friel O, Browne E, Fraughen DD, Murphy MP, Clarke J, Choileain ON, O'Connor E, McGuinness R, Boylan M, Kelly A, Hayden JC, Collins AM, Cullen A, Hyland D, Carroll TP, Geoghegan P, Laffey JG, Hennessy M, Martin-Loeches I, McElvaney NG, Curley GF. A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for ARDS secondary to COVID-19. Med. 2022 Apr 8;3(4):233-248.e6. doi: 10.1016/j.medj.2022.03.001. Epub 2022 Mar 11.
• Results Chapman KR, Burdon JG, Piitulainen E, Sandhaus RA, Seersholm N, Stocks JM, Stoel BC, Huang L, Yao Z, Edelman JM, McElvaney NG; RAPID Trial Study Group. Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jul 25;386(9991):360-8. doi: 10.1016/S0140-6736(15)60860-1. Epub 2015 May 27.
• Results Ritzmann F, Chitirala P, Kruger N, Hoffmann M, Zuo W, Lammert F, Smola S, Tov N, Alagem N, Lepper PM, Pohlmann S, Beisswenger C, Herr C, Bals R; AAT-in-COVID-19 Study Group. Therapeutic Application of Alpha-1 Antitrypsin in COVID-19. Am J Respir Crit Care Med. 2021 Jul 15;204(2):224-227. doi: 10.1164/rccm.202104-0833LE. No abstract available.
• Results McElvaney OJ, O'Connor E, McEvoy NL, Fraughan DD, Clarke J, McElvaney OF, Gunaratnam C, O'Rourke J, Curley GF, McElvaney NG. Alpha-1 antitrypsin for cystic fibrosis complicated by severe cytokinemic COVID-19. J Cyst Fibros. 2021 Jan;20(1):31-35. doi: 10.1016/j.jcf.2020.11.012. Epub 2020 Nov 20.
• Results Lockett AD, Kimani S, Ddungu G, Wrenger S, Tuder RM, Janciauskiene SM, Petrache I. alpha(1)-Antitrypsin modulates lung endothelial cell inflammatory responses to TNF-alpha. Am J Respir Cell Mol Biol. 2013 Jul;49(1):143-50. doi: 10.1165/rcmb.2012-0515OC.
• Results Pott GB, Chan ED, Dinarello CA, Shapiro L. Alpha-1-antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood. J Leukoc Biol. 2009 May;85(5):886-95. doi: 10.1189/jlb.0208145. Epub 2009 Feb 5.
• Results Nita I, Hollander C, Westin U, Janciauskiene SM. Prolastin, a pharmaceutical preparation of purified human alpha1-antitrypsin, blocks endotoxin-mediated cytokine release. Respir Res. 2005 Jan 31;6(1):12. doi: 10.1186/1465-9921-6-12.
• Results Janciauskiene S, Wrenger S, Immenschuh S, Olejnicka B, Greulich T, Welte T, Chorostowska-Wynimko J. The Multifaceted Effects of Alpha1-Antitrypsin on Neutrophil Functions. Front Pharmacol. 2018 Apr 17;9:341. doi: 10.3389/fphar.2018.00341. eCollection 2018.
• Results Aldonyte R, Jansson L, Janciauskiene S. Concentration-dependent effects of native and polymerised alpha1-antitrypsin on primary human monocytes, in vitro. BMC Cell Biol. 2004 Mar 29;5:11. doi: 10.1186/1471-2121-5-11.
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• Results McCarthy C, Reeves EP, McElvaney NG. The Role of Neutrophils in Alpha-1 Antitrypsin Deficiency. Ann Am Thorac Soc. 2016 Aug;13 Suppl 4:S297-304. doi: 10.1513/AnnalsATS.201509-634KV.
• Results Jonigk D, Al-Omari M, Maegel L, Muller M, Izykowski N, Hong J, Hong K, Kim SH, Dorsch M, Mahadeva R, Laenger F, Kreipe H, Braun A, Shahaf G, Lewis EC, Welte T, Dinarello CA, Janciauskiene S. Anti-inflammatory and immunomodulatory properties of alpha1-antitrypsin without inhibition of elastase. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15007-12. doi: 10.1073/pnas.1309648110. Epub 2013 Aug 23.
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Drugs

Indications