Inhaled colistimethate sodium in patients with bronchiectasis and Pseudomonas aeruginosa infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months.

Autor:	Haworth CS; Cambridge Centre for Lung Infection, Royal Papworth Hospital and University of Cambridge, Cambridge, UK., Shteinberg M; Pulmonology Institute and CF Center, Carmel Medical Center, Haifa, Israel; Technion Israel Institute of Technology, the B Rappaport Faculty of Medicine, Haifa, Israel., Winthrop K; Division of Infectious Diseases, Oregon Health and Science University, Portland, OR, USA., Barker A; Department of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR, USA., Blasi F; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Respiratory Unit and Cystic Fibrosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy., Dimakou K; 5th Respiratory Medicine Department, General Hospital for Chest Diseases of Athens Sotiria, Athens, Greece., Morgan LC; Department of Respiratory Medicine, Concord Repatriation General Hospital, Concord, NSW, Australia; University of Sydney, Sydney, NSW, Australia., O'Donnell AE; Division of Pulmonary, Critical Care and Sleep Medicine, Georgetown University Medical Center, Washington, DC, USA., Ringshausen FC; Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center of Lung Research, Hannover, Germany; European Reference Network on Rare and Complex Respiratory Diseases, Frankfurt, Germany., Sibila O; Department of Respiratory Medicine, Hospital Clinic of Barcelona, University of Barcelona, Centro de Investigacion Biomedica En Red Enfermedades Respiratorias, Institut d Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain., Thomson RM; Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Brisbane, QLD, Australia; University of Queensland, Brisbane, QLD, Australia., Carroll KJ; KJC Statistics Ireland, Dublin, Ireland., Pontenani F; Research and Development Department. Zambon SpA, Bresso, Milan, Italy., Castellani P; Research and Development Department. Zambon SpA, Bresso, Milan, Italy., Chalmers JD; Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK. Electronic address: j.chalmers@dundee.ac.uk.
Jazyk:	angličtina
Zdroj:	The Lancet. Respiratory medicine [Lancet Respir Med] 2024 Oct; Vol. 12 (10), pp. 787-798. Date of Electronic Publication: 2024 Sep 10.
DOI:	10.1016/S2213-2600(24)00225-X
Abstrakt:	Background: Chronic lung infection with Pseudomonas aeruginosa is associated with increased exacerbations and mortality in people with bronchiectasis. The PROMIS-I and PROMIS-II trials investigated the efficacy and safety of 12-months of inhaled colistimethate sodium delivered via the I-neb. Methods: Two randomised, double-blind, placebo-controlled trials of twice per day colistimethate sodium versus placebo were conducted in patients with bronchiectasis with P aeruginosa and a history of at least two exacerbations requiring oral antibiotics or one requiring intravenous antibiotics in the previous year in hospitals in Argentina, Australia, Belgium, Canada, France, Germany, Greece, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Spain, Switzerland, the UK, and the USA. Randomisation was conducted through an interactive web response system and stratified by site and long term use of macrolides. Masking was achieved by providing colistimethate sodium and placebo in identical vials. After random assignment, study visits were scheduled for 1, 3, 6, 9, and 12 months (the end of the treatment period); and telephone calls were scheduled for 7 days after random assignment and 2 weeks after the end of treatment. The primary endpoint was the mean annual exacerbation rate. These trials are registered with EudraCT: number 2015-002743-33 (for PROMIS-I) and 2016-004558-13 (for PROMIS-II), and are now completed. Findings: 377 patients were randomly assigned in PROMIS-I (177 to colistimethate sodium and 200 to placebo; in the modified intention-to-treat population, 176 were in the colistimethate sodium group and 197 were in the placebo group) between June 6, 2017, and April 8, 2020. The annual exacerbation rate was 0·58 in the colistimethate sodium group versus 0·95 in the placebo group (rate ratio 0·61; 95% CI 0·46-0·82; p=0·0010). 287 patients were randomly assigned in PROMIS-II (152 were assigned to colistimethate sodium and 135 were assigned to placebo, in the modified intention-to-treat population), between Feb 12, 2018, and Oct 22, 2021. PROMIS-II was then prematurely terminated due to the effect of the COVID-19 pandemic. No significant difference was observed in the annual exacerbation rate between the colistimethate sodium and placebo groups (0·89 vs 0·89; rate ratio 1·00; 95% CI 0·75-1·35; p=0·98). No major safety issues were identified. The overall frequency of adverse events was 142 (81%) patients in the colistimethate sodium group versus 159 (81%) patients in the placebo group in PROMIS-I, and 123 (81%) patients versus 104 (77%) patients in PROMIS-II. There were no deaths related to study treatment. Interpretation: The data from PROMIS-I suggest a clinically important benefit of colistimethate sodium delivered via the I-neb adaptive aerosol delivery system in patients with bronchiectasis and P aeruginosa infection. These results were not replicated in PROMIS-II, which was affected by the COVID-19 pandemic and prematurely terminated. Funding: Zambon. Competing Interests: Declaration of interests CSH reports consultancy or speakers fees from 30 Technology, AstraZeneca, CSL Behring, Chiesi, Infex, Insmed, Janssen, Lifearc, Meiji, Mylan, Pneumagen, Shionogi, Vertex, and Zambon. MS reports research grants from Glaxosmithkline, Trudell, and Tel Aviv League for Lung Disease; consulting fees or speaker fees for Astrazeneca, Boehringer Ingelheim, Dexcel, Kamada, Rafa, Synchrony Medical, Trumed, Vertex, Zambon, and Sanofi Insmed; and data safety monitoring board participation for Bonus Biotherapeutics and Boehringer Ingelheim. KW reports research grants from Insmed, Paratek, Red Hill Biopharma, AN2, Spero, and Renovion; consulting fees from Insmed, Paratek, Red Hill Biopharma, AN2, Renovion, Spero, Zambon, and Janssen; and data safety monitoring board participation for Janssen and Red Hill Biopharma. AB declares research funding from Zambon; and contributed to UptoDate. FB reports research funding from Astrazeneca, Glaxosmithkline, Chiesi, and Insmed; and consulting fees or speakers fees from Astrazeneca, Chiesi, Glaxosmithkline, Menarini, Grifols, Insmed, Novartis, Pfizer, Sanofi, Vertex, Viatris, and Zambon. KD reports payments for consultancy or lectures from Boehringer Ingelheim, GSK, Menarini, Novartis, Norma Hellas, Chiesi, Astrazeneca, and Zambon. LCM reports a leadership role with Lung Foundation Australia; research grants from Boehringer Ingelheim, Astrazeneca, Zambon, Insmed, and Glaxosmithkline; and consultancy or speaker fees from Boehringer Ingelheim, Astrazeneca, Zambon, Insmed, Sequirius, and Glaxosmithkline. AEO reports research grants from Zambon, Insmed, Boehringer Ingelheim, Armata, and the US COPD foundation; consultancy or speaker fees from Insmed, Boehringer Ingelheim, Zambon, and Electromed; participation in a data safety monitoring board for Paraxel; and fees from Academic CME, Vindico Medical Education, Answers in CME, Peer Review Institute, CE, and RMEI. FCR reports grant from the German Centre for Lung Research, German Centre for Infection Research, EU Innovative Medicines Initiative, Mukoviszidose Institute, Novartis, Insmed, Grifols, Bayer, and InfectoPharm; consulting fees or lecture fees from Parion, Grifols, Zambon, Insmed, Helmholtz-Zentrum fur Infektionsforschung, Astrazeneca, Insmed, and Grifols; participation in data safety monitoring board for Insmed, Grifols, Shionogi, and Boehringer Ingelheim; provided expert testimony to the Social Court Cologne; received support to attend meetings from German Kartagener Syndrome and Primary Ciliary Dyskinesia Patient Advocacy Group and Mukoviszidose; was a coordinator of the ERN-LUNG Bronchiectasis Core Network; was the chair of the German Bronchiectasis Registry PROGNOSIS; was a member of the SteerCo of the European Bronchiectasis Registry EMBARC and SteerCo of the European Nontuberculous Mycobacterial Pulmonary Disease Registry EMBARC-NTM; was a co-speaker of the Medical Advisory Board of the German Kartagener Syndrome and PCD Patient Advocacy Group; was a speaker of the Respiratory Infections and TB group of the German Respiratory Society, the Cystic Fibrosis group of German Respiratory Society (DGP); was a principal investigator of the German Center for Lung Research, Member of the Protocol Review Committee of the PCD-CTN, Member of Physician Association of the German Cystic Fibrosis Patient Advocacy Group; and declares fees to institution from clinical trial work from AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, German Center for Lung Research/KKS Marburg, Insmed, Novartis, Parion, University of Dundee, Vertex, and Zambon. RMT reports research grants from Australian Institute of Infectious Diseases, Herston Infectious Diseases Institute, Metro South Health, and the Asia Pacific Society of Respirology Gallipoli Medical Research Foundation; an eductional grant from Insmed; support for attending a meeting from Beyond Air; and consulting fees from AN2 Therapeutics, Beyond Air, and Insmed. KJC reports consulting fees from Zambon. FP is an employee of Zambon. PC is an employee of Zambon; and reports an international patent application WO 23/012280 in the name of Zambon, designating PC as the inventor. JDC has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed, and Trudell; and received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell, and Zambon. OS declares no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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