Clinical trial NCT02595060: Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) Inhalation to Improve Host Defense and Pulmonary Barrier Restoration
Official title: GM-CSF Inhalation to Improve Host Defense and Pulmonary Barrier Restoration (GI-HOPE). A Randomized, Double-blind, Parallel Group, Multicenter, Phase II Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: ARDS
Keywords: acute lung injury, molgramostim, GM-CSF, pneumonia, barrier restoration
Lead sponsor: University of Giessen
Sponsor class: OTHER
First posted: 2015-11-03
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial evaluates efficacy and safety of inhaled molgramostim (rhGM-CSF) in 45 patients with pneumonia associated acute respiratory distress syndrome (ARDS). A third of the patients will receive 150 mcg inhaled molgramostim, another third 450 mcg and the remaining third will receive inhaled placebo for 3 days. The patients will be followed for 28 days.


Eligibility criteria: Inclusion Criteria:

1. Signed informed consent form by the patient or a legal representative according to local regulations
2. Man or woman 18 to 75 years of age, inclusive
3. Women who have been post-menopausal for more than 1 year or women of childbearing potential period using a highly efficient method of contraception (i.e. a method with less than 1% failure rate such as combined hormonal contraception, progesterone-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tube occlusion, vasectomized partner, sexual abstinence) during dosing and hospitalisation. Women must have a negative serum or urine pregnancy test before the first dose of study medication and must not be lactating.
4. Diagnosis of pneumonia-associated ARDS, where the underlying condition is Community-Acquired Pneumonia (CAP) or Hospital-Acquired Pneumonia (HAP) in patients not on invasive ventilation upon diagnosis of HAP.
5. Diagnosis of ARDS according to the Berlin ARDS definition.
6. Requirement for positive pressure ventilation (non-invasive or via endotracheal tube) for more than 72 hours in total with inspiratory oxygen concentration (FiO2) ≥ 50% (or less when on additional ECMO therapy) not longer than 14 days

Exclusion Criteria:

1. Receiving vasopressors of \>100 µg/min
2. History of liver cirrhosis Child Pugh C, chronic hemodialysis (before severe pneumonia/ARDS), lung cancer
3. Malignancy with expected survival time of less than 6 months
4. History of or listing for lung transplantation
5. Highly immunosuppressive therapy or anti-malignant combination chemotherapy within 3 weeks prior to first dose of study drug
6. Any anti-malignant chemotherapy within 24 hours prior to first dose of study drug
7. AIDS or known history of HIV infection
8. Pregnancy
9. Autoimmune thrombocytopenia, myelodysplastic syndromes with \> 20% marrow blast cells
10. History or presence of hypersensitivity or idiosyncratic reaction to molgramostim or to related compounds (i.e., Growgen®, Leucomax®, Leukine™, Topleucon™)
11. Participation in another clinical trial within 90 days prior to the first dose of study drug

Primary outcomes:
measure: GI-HOPE score representing changes at Day 4/5 with respect to Baseline (Day -1)
timeFrame: baseline and Day 4/5
Secondary outcomes:
measure: Number of patients with Adverse Events (AE), Serious AEs and Adverse Drug Reactions
timeFrame: baseline to 28 days
measure: Oxygenation
timeFrame: Baseline to Day 11
measure: Acute Physiology and Chronic Health Evaluation (APACHE)
timeFrame: Baseline to Day 11
measure: Sequential Organ Failure Assessment (SOFA)
timeFrame: Baseline to Day 11
measure: Extravascular Lung Water Index
timeFrame: Baseline to Day 11
measure: C-reactive Protein
timeFrame: Baseline to Day 11
measure: Days on vasoactive drugs
timeFrame: Baseline to Day 28
measure: All cause mortality
timeFrame: Baseline to Day 28
measure: Serum GM-CSF
timeFrame: Baseline, Days 1-4
Other outcomes:
Locations:
city: Würzburg
country: Germany
facility: Klinik und Poliklinik für Anästhesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie
state: Baden-Würtemberg
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt, Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie
city: Giessen
country: Germany
facility: Universities of Marburg and Giessen Lung Center
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, Klinik für Intensivmedizin
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Klinik für Pneumologie
city: Jena
country: Germany
facility: Universitätsklinikum Jena, Klinik für Anästhesiologie und Intensivmedizin
city: Marburg
country: Germany
facility: University Hospital Marburg, Department of Anaesthesiology and Intensive Care Medicine
Study officials:
affiliation: Universities of Giessen and Marburg Lung Centers, Germany
name: Susanne Herold, Prof.Dr.med.,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Herold S, Hoegner K, Vadasz I, Gessler T, Wilhelm J, Mayer K, Morty RE, Walmrath HD, Seeger W, Lohmeyer J. Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome. Am J Respir Crit Care Med. 2014 Mar 1;189(5):609-11. doi: 10.1164/rccm.201311-2041LE. No abstract available.
citation: Cakarova L, Marsh LM, Wilhelm J, Mayer K, Grimminger F, Seeger W, Lohmeyer J, Herold S. Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte-macrophage colony-stimulating factor: impact on alveolar epithelial repair. Am J Respir Crit Care Med. 2009 Sep 15;180(6):521-32. doi: 10.1164/rccm.200812-1837OC. Epub 2009 Jul 9.
citation: Unkel B, Hoegner K, Clausen BE, Lewe-Schlosser P, Bodner J, Gattenloehner S, Janssen H, Seeger W, Lohmeyer J, Herold S. Alveolar epithelial cells orchestrate DC function in murine viral pneumonia. J Clin Invest. 2012 Oct;122(10):3652-64. doi: 10.1172/JCI62139. Epub 2012 Sep 10.
citation: Ballinger MN, Paine R 3rd, Serezani CH, Aronoff DM, Choi ES, Standiford TJ, Toews GB, Moore BB. Role of granulocyte macrophage colony-stimulating factor during gram-negative lung infection with Pseudomonas aeruginosa. Am J Respir Cell Mol Biol. 2006 Jun;34(6):766-74. doi: 10.1165/rcmb.2005-0246OC. Epub 2006 Feb 10.
citation: Standiford LR, Standiford TJ, Newstead MJ, Zeng X, Ballinger MN, Kovach MA, Reka AK, Bhan U. TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia. Am J Physiol Lung Cell Mol Physiol. 2012 Mar 1;302(5):L447-54. doi: 10.1152/ajplung.00415.2010. Epub 2011 Dec 9.