Inhaled Sargramostim (Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor) for COVID-19-Associated Acute Hypoxemia: Results of the Phase 2, Randomized, Open-Label Trial (iLeukPulm)
MD Robert Paine III, MD Robert Chasse, E Scott Halstead, MD Jay Nfonoyim, MD|| David J Park, MD Timothy Byun, MD Bela Patel, MD † † Guido Molina-Pallete, MD Estelle S Harris, PhD ‡ ‡ Fiona Garner, MSc, PStat, RAC (US) ‡ ‡ Lorinda Simms, MD ‡ ‡; Sanjeev Ahuja, John L Mcmanus, MD Debasish F Roychowdhury
Military Medicine, doi:10.1093/milmed/usac362
Introduction: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a protein produced in the lung, is essential for pulmonary host defense and alveolar integrity. Prior studies suggest potential benefits in several pulmonary conditions, including acute respiratory distress syndrome and viral infections. This trial evaluated the effect of the addition of inhaled sargramostim (yeast-derived, glycosylated recombinant human GM-CSF) to standard of care (SOC) on oxygenation and clinical outcomes in patients with COVID-19-associated acute hypoxemia.
Materials and Methods: A randomized, controlled, open-label trial of hospitalized adults with COVID-19-associated hypoxemia (oxygen saturation <93% on ≥2 L/min oxygen supplementation and/or PaO 2 /FiO 2 <350) randomized 2:1 to inhaled sargramostim (125 mcg twice daily for 5 days) plus SOC versus SOC alone. Institutional SOC before and during the study was not limited. Primary outcomes were change in the alveolar-arterial oxygen gradient (P(A-a)O 2 ) by day 6 and the percentage of patients intubated within 14 days. Safety evaluations included treatment-emergent adverse events. Efficacy analyses were based on the modified intent-to-treat population, the subset of the intent-to-treat population that received ≥1 dose of any study treatment (sargramostim and/or SOC). An analysis of covariance approach was used to analyze changes in oxygenation measures. The intubation rate was analyzed using the chi-squared test. All analyses are considered descriptive. The study was institutional review board approved.
Results: In total, 122 patients were treated (sargramostim, n = 78; SOC, n = 44). The sargramostim arm experienced greater improvement in P(A-a)O 2 by day 6 compared to SOC alone (least squares [LS] mean change from baseline [SE]: -102.3 [19.4] versus -30.5 [26.9] mmHg; LS mean difference: -71.7 [SE 33.2, 95% CI -137.7 to -5.8]; P = .033; n = 96). By day 14, 11.5% (9/78) of sargramostim and 15.9% (7/44) of SOC arms required intubation (P = .49). The 28-day mortality was 11.5% (9/78) and 13.6% (6/44) in the sargramostim and SOC arms, respectively (hazard ratio 0.85; P = .76). Treatment-emergent adverse events occurred in 67.9% (53/78) and 70.5% (31/44) on the sargramostim and SOC arms, respectively.
Conclusions: The addition of inhaled sargramostim to SOC improved P(A-a)O 2 , a measure of oxygenation, by day 6 in hospitalized patients with COVID-19-associated acute hypoxemia and was well tolerated. Inhaled sargramostim is delivered directly
SUPPLEMENTARY MATERIAL Supplementary material is available at Military Medicine online.
CONFLICT OF INTEREST STATEMENT The institutions for R.P., R.C., E. Scott Halstead, J.N., D.
CLINICAL TRIAL REGISTRATION NUMBER The trial was registered with ClinicalTrials.gov (NCT04411680) on May 29, 2020, with E. Scott Halstead, MD, PhD as the principal investigator.
INSTITUTIONAL REVIEW BOARD (HUMAN SUBJECTS) The
INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) Not applicable.
INDIVIDUAL AUTHOR CONTRIBUTION STATEMENT
INSTITUTIONAL CLEARANCE Institutional clearance does not apply.
References
Ali, Ali, Iqbal, COVID-19 vaccination: concerns about its accessibility, affordability, and acceptability, Front Med,
doi:10.3389/fmed.2021.647294Arentz, Yim, Klaff, Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington state, JAMA,
doi:10.1001/jama.2020.4326Armstrong, Kane, Kursumovic, Mortality in patients admitted to intensive care with COVID-19: an updated systematic review and meta-analysis of observational studies, Anaesthesia,
doi:10.1111/anae.15425Campo, Mariani, Paracchini, Whole lung lavage followed by inhaled sargramostim as therapy of autoimmune pulmonary alveolar proteinosis, Am J Respir Crit Care Med
Choi, Koch, Wu, Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis, Nat Med,
doi:10.1038/s41591-021-01527-yCriner, Lang, Gottlieb, Anti-granulocyte-macrophage colony-stimulating factor monoclonal antibody gimsilumab for COVID-19 pneumonia: a randomized, double-blind, placebocontrolled trial, Am J Respir Crit Care Med,
doi:10.1164/rccm.202108-1859OCDe Roos, Kilsdonk, Hekking, Chest computed tomography and alveolar-arterial oxygen gradient as rapid tools to diagnose and triage mildly symptomatic COVID-19 pneumonia patients, ERJ Open Res,
doi:10.1183/23120541.-00737-2020Hall, Joshi, Leal, Immune immunomodulation in coronavirus disease 2019 (COVID-19): strategic considerations for personalized therapeutic intervention, Clin Infect Dis,
doi:10.1093/cid/ciaa904Hall, Knatz, Vetterly, Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome, Intensive Care Med,
doi:10.1007/s00134-010--2088-xHalstead, Umstead, Davies, GM-CSF overexpression after influenza a virus infection prevents mortality and moderates M1-like airway monocyte/macrophage polarization, Respir Res,
doi:10.1186/s12931-017-0708-5Harris, Massie, Role of alveolar-arterial gradient in partial pressure of oxygen and PaO 2 /fraction of inspired oxygen ratio measurements in assessment of pulmonary dysfunction, AANA J
Herold, Hoegner, Vadasz, Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome, Am J Respir Crit Care Med,
doi:10.1164/rccm.201311-2041LEKim, Garg, 'halloran, Risk factors for intensive care unit admission and in-hospital mortality among hospitalized adults identified through the US Coronavirus Disease 2019 (COVID-19)-Associated Hospitalization Surveillance Network (COVID-NET), Clin Infect Dis,
doi:10.1093/cid/ciaa1012Lee, Miller, Ataya, Opportunistic infection associated with elevated GM-CSF autoantibodies: a case series and review of the literature, Open Forum Infect Dis,
doi:10.1093/ofid/ofac146Mackey, Ayers, Kondo, Racial and ethnic disparities in COVID-19-related infections, hospitalizations, and deaths: a systematic review, Ann Intern Med,
doi:10.7326/M20-6306Meisel, Schefold, Pschowski, Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial, Am J Respir Crit Care Med,
doi:10.1164/rccm.200903-0363OCPaine, Standiford, Dechert, A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury, Crit Care Med,
doi:10.1097/CCM.0b013e31822d7bf0Rosik, Lechowicz, An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment, Drug Resist Updat,
doi:10.1016/j.drup.2021.100794Rosler, Herold, Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumoniaa new therapeutic strategy?, Mol Cell Pediatr,
doi:10.1186/s40348-016-0055-5Schneider, Nobs, Kurrer, Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages, Nat Immunol,
doi:10.1038/ni.3005Siemieniuk, Bartoszko, Ge, Drug treatments for covid-19: living systematic review and network meta-analysis, BMJ,
doi:10.1136/bmj.m2980Tazawa, Trapnell, Inoue, Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis, Am J Respir Crit Care Med,
doi:10.1164/rccm.200906-0978OCTriggle, Bansal, Ding, A comprehensive review of viral characteristics, transmission, pathophysiology, immune response, and management of SARS-CoV-2 and COVID-19 as a basis for controlling the pandemic, Front Immunol,
doi:10.3389/fimmu.2021.631139Tzotzos, Fischer, Fischer, Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey, Crit Care,
doi:10.1186/s13054-020-03240-7Unkel, Hoegner, Clausen, Alveolar epithelial cells orchestrate DC function in murine viral pneumonia, J Clin Invest,
doi:10.1172/JCI62139Weinreich, Sivapalasingam, Norton, REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19, N Engl J Med,
doi:10.1056/NEJMoa2035002Wessendarp, Watanabe-Chailland, Liu, Role of GM-CSF in regulating metabolism and mitochondrial functions critical to macrophage proliferation, Mitochondrion,
doi:10.1016/j.mito.2021.10.009Zhou, Yu, Du, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet,
doi:10.1016/S0140-6736(20)30566-3{ 'indexed': {'date-parts': [[2024, 3, 8]], 'date-time': '2024-03-08T10:47:06Z', 'timestamp': 1709894826330},
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'abstract': '<jats:title>ABSTRACT</jats:title>\n'
' <jats:sec>\n'
' <jats:title>Introduction</jats:title>\n'
' <jats:p>Granulocyte-macrophage colony-stimulating factor (GM-CSF), a '
'protein produced in the lung, is essential for pulmonary host defense and alveolar integrity. '
'Prior studies suggest potential benefits in several pulmonary conditions, including acute '
'respiratory distress syndrome and viral infections. This trial evaluated the effect of the '
'addition of inhaled sargramostim (yeast-derived, glycosylated recombinant human GM-CSF) to '
'standard of care (SOC) on oxygenation and clinical outcomes in patients with '
'COVID-19-associated acute hypoxemia.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Materials and Methods</jats:title>\n'
' <jats:p>A randomized, controlled, open-label trial of hospitalized adults '
'with COVID-19-associated hypoxemia (oxygen saturation &lt;93% on ≥2\u2009L/min oxygen '
'supplementation and/or PaO2/FiO2 &lt;350) randomized 2:1 to inhaled sargramostim '
'(125\u2009mcg twice daily for 5\u2009days) plus SOC versus SOC alone. Institutional SOC '
'before and during the study was not limited. Primary outcomes were change in the '
'alveolar–arterial oxygen gradient (P(A–a)O2) by day 6 and the percentage of patients '
'intubated within 14\u2009days. Safety evaluations included treatment-emergent adverse events. '
'Efficacy analyses were based on the modified intent-to-treat population, the subset of the '
'intent-to-treat population that received ≥1 dose of any study treatment (sargramostim and/or '
'SOC). An analysis of covariance approach was used to analyze changes in oxygenation measures. '
'The intubation rate was analyzed using the chi-squared test. All analyses are considered '
'descriptive. The study was institutional review board approved.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>In total, 122 patients were treated (sargramostim, n\u2009=\u2009'
'78; SOC, n\u2009=\u200944). The sargramostim arm experienced greater improvement in P(A–a)O2 '
'by day 6 compared to SOC alone (least squares [LS] mean change from baseline [SE]: −102.3 '
'[19.4] versus −30.5 [26.9] mmHg; LS mean difference: −71.7 [SE 33.2, 95% CI −137.7 to −5.8]; '
'P\u2009=\u2009.033; n\u2009=\u200996). By day 14, 11.5% (9/78) of sargramostim and 15.9% '
'(7/44) of SOC arms required intubation (P\u2009=\u2009.49). The 28-day mortality was 11.5% '
'(9/78) and 13.6% (6/44) in the sargramostim and SOC arms, respectively (hazard ratio 0.85; '
'P\u2009=\u2009.76). Treatment-emergent adverse events occurred in 67.9% (53/78) and 70.5% '
'(31/44) on the sargramostim and SOC arms, respectively.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>The addition of inhaled sargramostim to SOC improved P(A–a)O2, a '
'measure of oxygenation, by day 6 in hospitalized patients with COVID-19-associated acute '
'hypoxemia and was well tolerated. Inhaled sargramostim is delivered directly to the lung, '
'minimizing systemic effects, and is simple to administer making it a feasible treatment '
'option in patients in settings where other therapy routes may be difficult. Although '
'proportionally lower rates of intubation and mortality were observed in sargramostim-treated '
'patients, this study was insufficiently powered to demonstrate significant changes in these '
'outcomes. However, the significant improvement in gas exchange with sargramostim shows this '
'inhalational treatment enhances pulmonary efficiency in this severe respiratory illness. '
'These data provide strong support for further evaluation of sargramostim in high-risk '
'patients with COVID-19.</jats:p>\n'
' </jats:sec>',
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'critical for the differentiation of fetal monocytes into alveolar '
'macrophages',
'volume': '15',
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'key': '2023072301103648900_R15',
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'doi-asserted-by': 'publisher',
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'doi-asserted-by': 'publisher',
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'of pneumonia-associated acute respiratory distress syndrome',
'volume': '189',
'author': 'Herold',
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