David E Griffith1, Gina Eagle2, Rachel Thomson3, Timothy R Aksamit4, Naoki Hasegawa5, Kozo Morimoto6, Doreen J Addrizzo-Harris7, Anne E O'Donnell8, Theodore K Marras9, Patrick A Flume10, Michael R Loebinger11, Lucy Morgan12, Luigi R Codecasa13, Adam T Hill14, Stephen J Ruoss15, Jae-Joon Yim16, Felix C Ringshausen17, Stephen K Field18, Julie V Philley1, Richard J Wallace1, Jakko van Ingen19, Chris Coulter20, James Nezamis2, Kevin L Winthrop21. 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.
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).
RCT Entities:
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 MAClung disease. Methods: Adults with amikacin-susceptible MAClung 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 MAClung 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).
Authors: Hee Jae Huh; Su-Young Kim; Hyang Jin Shim; Dae Hun Kim; In Young Yoo; On-Kyun Kang; Chang-Seok Ki; So Youn Shin; Byung Woo Jhun; Sung Jae Shin; Charles L Daley; Won-Jung Koh; Nam Yong Lee Journal: J Clin Microbiol Date: 2019-07-26 Impact factor: 5.948
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Authors: Charles L Daley; Jonathan M Iaccarino; Christoph Lange; Emmanuelle Cambau; Richard J Wallace; Claire Andrejak; Erik C Böttger; Jan Brozek; David E Griffith; Lorenzo Guglielmetti; Gwen A Huitt; Shandra L Knight; Philip Leitman; Theodore K Marras; Kenneth N Olivier; Miguel Santin; Jason E Stout; Enrico Tortoli; Jakko van Ingen; Dirk Wagner; Kevin L Winthrop Journal: Eur Respir J Date: 2020-07-07 Impact factor: 16.671
Authors: Charles L Daley; Jonathan M Iaccarino; Christoph Lange; Emmanuelle Cambau; Richard J Wallace; Claire Andrejak; Erik C Böttger; Jan Brozek; David E Griffith; Lorenzo Guglielmetti; Gwen A Huitt; Shandra L Knight; Philip Leitman; Theodore K Marras; Kenneth N Olivier; Miguel Santin; Jason E Stout; Enrico Tortoli; Jakko van Ingen; Dirk Wagner; Kevin L Winthrop Journal: Clin Infect Dis Date: 2020-08-14 Impact factor: 9.079