GM-CSF Inhalation to Prevent ARDS in COVID-19 Pneumonia

COVID-19 Pneumonia Clinical Trial

— GI-COVID  

Official title:

Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Inhalation to Prevent ARDS in COVID-19 Pneumonia (GI-COVID)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04569877
• Other study ID #: KKS-279
• Secondary ID: 2020-001654-21
• Status: Completed
• Phase: Phase 2
• Start date: September 24, 2020
• Est. completion date: September 20, 2022

Study information

• Verified date: June 2022
• Source: University of Giessen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To assess the safety and tolerability of inhaled molgramostim nebuliser solution in patients with COVID-19 pneumonia.

Description:

COVID-19 pneumonia is induced by the newly emerging pandemic Severe acute respiratory Syndrome (SARS) coronavirus 2 and results in progression to the acute respiratory distress syndrome (ARDS). Apart from protective ventilation, fluid restriction, prone positioning and extracorporeal membrane oxygenation (ECMO), no specific therapeutic options exist to treat this devastating disease with a mortality rate of up to 50%. The growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) is widely recognized to promote differentiation and mobilization of different myeloid leukocyte subsets including neutrophils, tissue macrophages/dendritic cells or their circulating precursors. GM-CSF was found to be crucial for alveolar epithelial repair following hyperoxic and inflammatory lung injury.The aim of the current trial is to prevent progression to ARDS in COVID-19 pneumonia patients by preemptive GM-CSF Inhalation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: September 20, 2022
• Est. primary completion date: June 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Signed informed consent form by the patient according to local regulations

2. Man or non-pregnant woman

3. Age =18 years

4. Willingness of patients with reproductive potential to use highly effective contraceptive methods by practicing abstinence or by using at least two methods of birth control from the date of consent to the end of the study. If abstinence could not be practiced, a combination of hormonal contraceptive (oral, injectable, or implants) and a barrier method (condom, diaphragm with a vaginal spermicidal agent) has to be used *.

5. Lab-confirmed COVID-19 pneumonia where pneumonia is diagnosed by radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR clinical assessment (evidence of rales/crackles on exam) AND pulse oximeter oxygen saturation = 94% at room air in patients that do not have chronic hypoxia; or less than their baseline oxygenation in patients that suffer from chronic hypoxia

6. Negative serum pregnancy test in women of childbearing potentia

Exclusion Criteria:

1. Pregnancy or breast feeding

2. Autoimmune thrombocytopenia, myelodysplastic syndromes with > 20% marrow blast cells

3. History or presence of hypersensitivity or idiosyncratic reaction to molgramostim (e.g. Leucomax®) or to related compounds (e.g. Leukine®)

4. Patient not able to use nebulizer device as well as immediately foreseeable mechanical ventilation of the patient

5. Simultaneous participation in another clinical trial with an experimental treatment

Related Conditions & MeSH terms

• COVID-19
• COVID-19 Pneumonia
• Pneumonia
• Severe Acute Respiratory Syndrome
• Severe Acute Respiratory Syndrome (SARS) Pneumonia

Intervention

Drug:
• Molgramostim nebuliser solution
300µg molgramostim nebuliser solution nebulised seven times within 7 days via rapid nebuliser system

Other:
• Placebo nebuliser solution
Placebo nebulised seven times within 7 days via rapid nebuliser system

Locations

Country	Name	City	State
Germany	Universitätsklinikum Carl Gustav Carus Dresden	Dresden
Germany	Universitätsklinikum Essen	Essen
Germany	Krankenhaus Nordwest GmbH	Frankfurt am Main
Germany	Universitätsklinikum Frankfurt	Frankfurt am Main
Germany	Universitätsklinikum Giessen und Marburg GmbH, Standort Giessen	Gießen
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Lungenfachklinik Immenhausen	Immenhausen
Germany	Sana Klinikum Offenbach	Offenbach am Main

Sponsors (1)

Lead Sponsor	Collaborator
University of Giessen

Country where clinical trial is conducted

Germany, 

References & Publications (11)

Arndt CA, Koshkina NV, Inwards CY, Hawkins DS, Krailo MD, Villaluna D, Anderson PM, Goorin AM, Blakely ML, Bernstein M, Bell SA, Ray K, Grendahl DC, Marina N, Kleinerman ES. Inhaled granulocyte-macrophage colony stimulating factor for first pulmonary recurrence of osteosarcoma: effects on disease-free survival and immunomodulation. a report from the Children's Oncology Group. Clin Cancer Res. 2010 Aug 1;16(15):4024-30. doi: 10.1158/1078-0432.CCR-10-0662. Epub 2010 Jun 24. — View 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. — View 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. — View Citation

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28. — View Citation

Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. 2008 Jul;8(7):533-44. doi: 10.1038/nri2356. — View 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. — View Citation

Huang FF, Barnes PF, Feng Y, Donis R, Chroneos ZC, Idell S, Allen T, Perez DR, Whitsett JA, Dunussi-Joannopoulos K, Shams H. GM-CSF in the lung protects against lethal influenza infection. Am J Respir Crit Care Med. 2011 Jul 15;184(2):259-68. doi: 10.1164/rccm.201012-2036OC. Epub 2011 Apr 7. — View Citation

LeVine AM, Reed JA, Kurak KE, Cianciolo E, Whitsett JA. GM-CSF-deficient mice are susceptible to pulmonary group B streptococcal infection. J Clin Invest. 1999 Feb;103(4):563-9. doi: 10.1172/JCI5212. — View Citation

Matute-Bello G, Liles WC, Radella F 2nd, Steinberg KP, Ruzinski JT, Hudson LD, Martin TR. Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med. 2000 Jan;28(1):1-7. doi: 10.1097/00003246-200001000-00001. — View Citation

Papiris SA, Tsirigotis P, Kolilekas L, Papadaki G, Papaioannou AI, Triantafillidou C, Papaporfyriou A, Karakatsani A, Kagouridis K, Griese M, Manali ED. Long-term inhaled granulocyte macrophage-colony-stimulating factor in autoimmune pulmonary alveolar proteinosis: effectiveness, safety, and lowest effective dose. Clin Drug Investig. 2014 Aug;34(8):553-64. doi: 10.1007/s40261-014-0208-z. — View Citation

Presneill JJ, Harris T, Stewart AG, Cade JF, Wilson JW. A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Am J Respir Crit Care Med. 2002 Jul 15;166(2):138-43. doi: 10.1164/rccm.2009005. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mechanical ventilation	Need for mechanical ventilation within 15 days after randomization	During 15 days
Secondary	Clinical status of subject at day 15 and day 29 (on a 7-point ordinal scale):	Not hospitalized, no limitations on activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death.	At day 15 and day 29
Secondary	Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] will be measured at day 0 (day before first dose), day 1-9, and day 15	At day 0 (day before first dose), day 1-9, and day 15
Secondary	Oxygen supply	Need for oxygen supply (l/min) to reach peripheral oxygen saturation of 98%	At day 0, day 1-7, day 8-9 (24 hours/48 hours post dose) and day 15
Secondary	Clinical parameter: temperature	Clinical parameter (4 times daily): temperature (°C degree)	Max. 48 hours before day 0, at day 0, day 1-7, day 8-9 and day 15
Secondary	Clinical parameter: blood pressure	Clinical parameter (4 times daily): blood pressure (mmHg)	Max. 48 hours before day 0, at day 0, day 1-7, day 8-9 and day 15
Secondary	Clinical parameter: heart beat	Clinical parameter (4 times daily): hear beat (beats per minute)	Max. 48 hours before day 0, at day 0, day 1-7, day 8-9 and day 15
Secondary	Clinical parameter: respiratory rate	Clinical parameter (4 times daily): respiratory rate (breaths per minute)	Max. 48 hours before day 0, at day 0, day 1-7, day 8-9 and day 15
Secondary	Severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (PCR)	Presence of Severe acute respiratory syndrome coronavirus 2 nucleic acid by PCR test in swabs or tracheal aspirates/bronchoalveolar lavage	Max. 48 hours before day 0 and at day 8-9
Secondary	Laboratory: C-reactive protein test	C-reactive protein test measures the amount of C-reactive protein in blood (mg/L)	At day 0, day 1-7, day 8-9 and day 15
Secondary	Laboratory: ferritin	Ferritin test measures the amount of ferritin in the blood (ng/ml)	At day 0, day 1-7, day 8-9 and day 15
Secondary	Laboratory: Interleukin-6	Interleukin-6 test (IL-6) measures the amount of IL-6 in the blood (pg/ml)	At day 0, day 1-7, day 8-9 and day 15
Secondary	Laboratory: procalcitonin	Procalcitonin (PCT) test measures the amount of PCT in the blood in (µg/l)	At day 0, day 1-7, day 8-9 and day 15
Secondary	Bacterial pneumonia	Occurrence of secondary bacterial pneumonia	At day 0, day 1-7, day 8-9 and day 15
Secondary	Vaso-active drugs	Days on vaso-active drugs in a 29-day period	At day 29
Secondary	Mortality	All-cause mortality	At day 29
Secondary	GM-CSF	GM-CSF levels in serum	At day 0 and day 1-7