Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE)

Noel G McElvaney; Jonathan Burdon; Mark Holmes; Allan Glanville; Peter A B Wark; Philip J Thompson; Paul Hernandez; Jan Chlumsky; Helmut Teschler; Joachim H Ficker; Niels Seersholm; Alan Altraja; Riitta Mäkitaro; Joanna Chorostowska-Wynimko; Marek Sanak; Paul I Stoicescu; Eeva Piitulainen; Oliver Vit; Marion Wencker; Michael A Tortorici; Michael Fries; Jonathan M Edelman; Kenneth R Chapman; RAPID Extension Trial Group

doi:10.1016/S2213-2600(16)30430-1

Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 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.

Authors

Noel G McElvaney¹, Jonathan Burdon², Mark Holmes³, Allan Glanville⁴, Peter A B Wark⁵, Philip J Thompson⁶, Paul Hernandez⁷, Jan Chlumsky⁸, Helmut Teschler⁹, Joachim H Ficker¹⁰, Niels Seersholm¹¹, Alan Altraja¹², Riitta Mäkitaro¹³, Joanna Chorostowska-Wynimko¹⁴, Marek Sanak¹⁵, Paul I Stoicescu¹⁶, Eeva Piitulainen¹⁷, Oliver Vit¹⁸, Marion Wencker¹⁹, Michael A Tortorici²⁰, Michael Fries²⁰, Jonathan M Edelman²⁰, Kenneth R Chapman²¹; RAPID Extension Trial Group

Affiliations

¹ Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland. Electronic address: gmcelvaney@rcsi.ie.
² St Vincent's Hospital, Department of Respiratory Medicine, Fitzroy, VIC, Australia.
³ University of Adelaide and Royal Adelaide Hospital, Department of Thoracic Medicine, Respiratory Clinical Trials Unit, Adelaide, SA, Australia.
⁴ St Vincent's Hospital, Department of Lung Transplantation and Thoracic Medicine, Darlinghurst, NSW, Australia.
⁵ Hunter Medical Research Institute, Centre for Asthma and Respiratory Disease, New Lambton, NSW, Australia.
⁶ Institute of Respiratory Medicine & School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia.
⁷ Dalhousie University, Division of Respirology, Halifax, NS, Canada.
⁸ Thomayer Hospital, First Medical Faculty, Charles University, Department of Pulmonary Diseases, Prague, Czech Republic.
⁹ Ruhrlandklinik, Department of Pneumology, West German Lung Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
¹⁰ Department of Respiratory Medicine, Allergology and Sleep Medicine, General Hospital Nuernberg, Nuremberg, Germany.
¹¹ Gentofte Hospital, Pulmonary Department Y, Hellerup, Denmark.
¹² University of Tartu, Department of Pulmonary Medicine, Tartu, Estonia.
¹³ Oulu University Hospital, Department of Internal Medicines, Oulu, Finland.
¹⁴ National Institute of Tuberculosis and Lung Diseases, Department of Genetics and Clinical Immunology, Warsaw, Poland.
¹⁵ Jagiellonian University Medical College, Division of Molecular Biology and Clinical Genetics, Krakow, Poland.
¹⁶ Sanador S A Clinical, Central Medical Clinica II, Bucharest, Romania.
¹⁷ Skane University Hospital, Department of Respiratory Medicine, Lund University, Malmö, Sweden.
¹⁸ CSL Behring, Bern, Switzerland.
¹⁹ conresp, Mainz, Germany.
²⁰ CSL Behring, King Of Prussia, PA, USA.
²¹ Asthma & Airway Centre, University Health Network and University of Toronto, Toronto, Canada.

PMID: 27916480
DOI: 10.1016/S2213-2600(16)30430-1

Abstract

Background: Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT.

Methods: Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007.

Findings: Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; -1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and -1·60 g/L per year [0·26] at FRC) than in the delayed-start group (-2·26 g/L per year [0·27] at TLC; -2·16 g/L per year [0·26] at TLC plus FRC, and -2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48.

Interpretation: RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment.

Funding: CSL Behring.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Disease Progression
Female
Humans
Lung / pathology
Lung / physiopathology
Male
Pulmonary Emphysema / congenital
Pulmonary Emphysema / drug therapy*
Pulmonary Emphysema / pathology
Regression Analysis
Respiratory Function Tests
Serine Proteinase Inhibitors / administration & dosage*
Total Lung Capacity
Treatment Outcome
Young Adult
alpha 1-Antitrypsin / administration & dosage*
alpha 1-Antitrypsin Deficiency / complications*
alpha 1-Antitrypsin Deficiency / pathology

Substances

Serine Proteinase Inhibitors
alpha 1-Antitrypsin

Associated data

ClinicalTrials.gov/NCT00670007