Inhaled GM-CSF (Molgramostim) as host-directed therapy for pneumonia-related ARDS A multicenter, randomized, placebo-controlled phase 2a trial (GI-HOPE)

GM-CSF enhances pulmonary host defense and promotes re-establishment of alveolar barrier function. We investigated safety, feasibility and efficacy of nebulized recombinant human (rh)GM-CSF/Molgramostim in pneumonia-related ARDS. In this multicenter/randomized/double-blind/parallel-group/placebo-controlled investigator-initiated phase IIa trial, patients were randomized to receive nebulized low-dose (150mcg) or high-dose (450mcg) rhGM-CSF or placebo for 3d. BAL was performed before first and after dosing. Primary outcome parameter was the composite GI-HOPE score, representing expression changes of CD80/CD86/CD206/HLA-DR on alveolar macrophages after dosing compared to baseline.Secondary outcomes included oxygenation, SOFA scores, and clinical endpoints at d28. 46 participants were randomized, 43 completed treatment (n=15 placebo, n=15 low-dose, n=13 high-dose), and BAL was performed on 38 participants before and after treatment. Although the composite biological GI-HOPE score did not reach significance (p>0.05), high-dose treatment caused upregulation of HLA-DR and CD206 on alveolar macrophages, indicating deposition in the alveolar compartment and beneficial macrophage activation (HLA-DR: p=0.0406 versus low-dose; p=0.1841 versus placebo; CD206: p=0.009 versus low-dose; p=0.0179 versus placebo). High-dose rhGM-CSF treatment revealed a favourable profile of oxygenation at the end of analysis compared to time points before inhalation (p=0.095 and p=0.0175), or compared to low-dose and placebo groups (p=0.0063 and p=0.0198; v13), and was associated with decreased SOFA scores in the high-dose group over time (p=0.0013 and p=0.001 compared to low-dose/placebo). Importantly, inhaled rhGM-CSF did not increase alveolar or systemic inflammation. Inhalation of 450mcg rhGM-CSF was safe,promoted a favourable profile regarding alveolar macrophage activation, oxygenation, and SOFA scores over time, however did not lead to differences in the GI-HOPE score. Funded by DZL and Savara Pharmaceuticals ( NCT02595060 , www.clinicaltrials.gov )