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. 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.
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) orplacebo (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 theUSA 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.
RCT Entities:
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.
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