Inhaled molgramostim therapy in autoimmune pulmonary alveolar proteinosis

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DOI

  • B. C. Trapnell, Cincinnati Children's Hospital Medical Center
  • ,
  • Y. Inoue, National Hospital Organization, Japan
  • ,
  • F. Bonella, University of Duisburg-Essen
  • ,
  • C. Morgan, Departments of Critical Care and Respiratory Medicine, Imperial College London
  • ,
  • S. Jouneau, Universite de Rennes 1
  • ,
  • E. Bendstrup
  • I. Campo, IRCCS Fondazione Policlinico San Matteo - Pavia
  • ,
  • S. A. Papiris, University of Athens
  • ,
  • E. Yamaguchi, Aichi Medical University Hospital
  • ,
  • E. Cetinkaya, University of Health Sciences Turkey
  • ,
  • M. M. Ilkovich, Pavlov First State Medical University of St. Petersburg
  • ,
  • M. R. Kramer, Institute of Pulmonary and Allergy Medicine, Rabin Medical Center Israel
  • ,
  • M. Veltkamp, St. Antonius Ziekenhuis
  • ,
  • M. Kreuter, Heidelberg University 
  • ,
  • T. Baba, Kanagawa Cardiovascular and Respiratory Center
  • ,
  • C. Ganslandt, Savara Pharmaceuticals
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  • I. Tarnow, Savara Pharmaceuticals
  • ,
  • G. Waterer, University of Western Australia
  • ,
  • T. Jouhikainen, Savara
  • ,
  • IMPALA Trial Investigators

BACKGROUND Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP. METHODS In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24. RESULTS In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group. CONCLUSIONS In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).

Original languageEnglish
JournalNew England Journal of Medicine
Volume383
Issue17
Pages (from-to)1635-1644
Number of pages10
ISSN0028-4793
DOIs
Publication statusPublished - Oct 2020

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