Amikacin Liposome Inhalation Suspension for Treatment-Refractory Lung Disease Caused by Mycobacterium avium Complex (CONVERT). A Prospective, Open-Label, Randomized Study

  • Am J Respir Crit Care Med. 2018 Dec 15;198(12):1559-1569. doi: 10.1164/rccm.201807-1318OC.
David E Griffith  1 ,  Gina Eagle  2 ,  Rachel Thomson  3 ,  Timothy R Aksamit  4 ,  Naoki Hasegawa  5 ,  Kozo Morimoto  6 ,  Doreen J Addrizzo-Harris  7 ,  Anne E O'Donnell  8 ,  Theodore K Marras  9 ,  Patrick A Flume  10 ,  Michael R Loebinger  11 ,  Lucy Morgan  12 ,  Luigi R Codecasa  13 ,  Adam T Hill  14 ,  Stephen J Ruoss  15 ,  Jae-Joon Yim  16 ,  Felix C Ringshausen  17 ,  Stephen K Field  18 ,  Julie V Philley  1 ,  Richard J Wallace Jr  1 ,  Jakko van Ingen  19 ,  Chris Coulter  20 ,  James Nezamis  2 ,  Kevin L Winthrop  21 ,  CONVERT Study Group
Affiliations
  • 1. 1 The University of Texas Health Science Center at Tyler, Tyler, Texas.
  • 2. 2 Insmed Incorporated, Bridgewater, New Jersey.
  • 3. 3 University of Queensland, Gallipoli Medical Research Institute, Brisbane, Queensland, Australia.
  • 4. 4 Pulmonary Disease and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.
  • 5. 5 Keio University Hospital, Tokyo, Japan.
  • 6. 6 Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.
  • 7. 7 Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of Medicine, New York, New York.
  • 8. 8 Division of Pulmonary, Critical Care and Sleep Medicine, Georgetown University Hospital, Washington, District of Columbia.
  • 9. 9 Department of Medicine, University of Toronto, and Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
  • 10. 10 Medical University of South Carolina, Charleston, South Carolina.
  • 11. 11 Host Defense Unit, Royal Brompton Hospital, and Imperial College, London, United Kingdom.
  • 12. 12 Concord Clinical School, University of Sydney, Sydney, New South Wales, Australia.
  • 13. 13 TB Reference Centre, Villa Marelli Institute/Niguarda Hospital, Milan, Italy.
  • 14. 14 Department of Respiratory Medicine, Royal Infirmary of Edinburgh and Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
  • 15. 15 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California.
  • 16. 16 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
  • 17. 17 Department of Respiratory Medicine, Hannover Medical School, and German Center for Lung Research, Hannover, Germany.
  • 18. 18 Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • 19. 19 Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 20. 20 Queensland Mycobacterium Reference Laboratory, Pathology Queensland, Brisbane, Australia; and.
  • 21. 21 OHSU-PSU School of Public Health, Portland, Oregon.
PMID: 30216086 DOI: 10.1164/rccm.201807-1318OC
Abstract

Rationale: Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives: To evaluate the efficacy and safety of daily amikacin Liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Methods: Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Measurements and Main Results: Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08-8.57; P < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Conclusions: Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).

Keywords
ALIS; culture conversion; guideline-based therapy; liposomal amikacin for inhalation; nontuberculous mycobacteria.
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