Phase IV study to evaluate the effectiveness of additional inhaled sargramostim (GM-CSF) versus standard of care on blood oxygenation in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure.
Leukine® is a yeast-derived recombinant humanized granulocyte-macrophage colony stimulating
factor (rhuGM-CSF, sargramostim) and the only FDA approved GM-CSF. GMCSF, a pleiotropic
cytokine, is an important leukocyte growth factor known to play a key role in hematopoiesis,
effecting the growth and maturation of multiple cell lineages as well as the functional
activities of these cells in antigen presentation and cell mediated immunity.
Leukine inhalation or intravenous administration, as an adjuvant therapy, may confer benefit
to patients with ARDS (Acute Respiratory Distress Syndrome) due to COVID-19 exposure, who are
at significant risk of mortality. While there is no active IND (Investigational New Drug) for
Leukine in the proposed patient population, Leukine is being studied in Fase II as an
adjuvant therapy in the management of life-threatening infections to boost the hosts innate
immune response to fight infection, reduce the risk of secondary infection, and in varied
conditions as prevention of infection during critical illness. Inhaled Leukine has also been
successfully used as primary therapy to improve oxygenation in patients with disordered gas
exchange in the lungs. We propose that based on preclinical and clinical data, Leukine
inhalation, as an adjuvant therapy, has an acceptable benefit-risk for use in patients with
hypoxic respiratory failure and ARDS due to COVID-19 exposure, who are at significant risk of
mortality.
Confirmed COVID19 patients with hypoxic respiratory failure (saturation below 93% on minimal
2 l/min O2) will be randomized to receive sargramostim 125mcg twice daily for 5 days as a
nebulized inhalation on top of standard of care, or to receive standard of care treatment.
Upon progression of disease requiring initiation of mechanical ventilatory support within the
5 day period, in patients in the active group, inhaled sargramostim will be replaced by
intravenous sargramostim 125mcg/m2 body surface area until the 5 day period is reached. From
day 6 onwards, progressive patients in the active group will have the option to receive an
additional 5 days of IV sargramostim, based on the treating physician's assessment. In the
control group progressive disease requiring mechanical ventilatory support, from day 6
onwards, the treating physician will have the option to initiate IV sargramostim 125mcg/m2
body surface area for 5 days. Safety data, including blood leukocyte counts, will be
collected in all patients. Efficacy data will also be collected and will include arterial
blood gases, oxygenation parameters, need for ventilation, lung compliance, organ function,
radiographic changes, ferritin levels, etc. as well as occurrence of secondary bacterial
infections.
Drug: Sargramostim
Inhalation via mesh nebulizer and/or IV administration upon Clinical deterioration
Other Name: LEUKINE
Other: Control
Standard of care
Inclusion Criteria:
- Recent (≤2weeks prior to Randomization) confident diagnosis of COVID-19 confirmed by
antigen detection and/or PCR (Polymerase Chain Reaction), and/or seroconversion or any
other emerging and validated diagnostic test
- In some patients, it may be impossible to get a confident laboratory confirmation of
COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or
problems with diagnostic sensitivity. In those cases, in absence of an alternative
diagnosis, and with highly suspect bilateral ground glass opacities on recent (<24h)
chest-CT scan (confirmed by a radiologist and pulmonary physician as probable
COVID-19), a patient can be enrolled as probable COVID-19 infected. In all cases, this
needs confirmation by later seroconversion.
- Presence of acute hypoxic respiratory failure defined as (either or both)
- saturation below 93% on minimal 2 l/min O2
- PaO2/FiO2 below 300
- Admitted to specialized COVID-19 ward
- Age 18-80
- Male or Female
- Willing to provide informed consent
Exclusion Criteria:
- Patients with known history of serious allergic reactions, including anaphylaxis, to
human granulocyte-macrophage colony stimulating factor such as sargramostim,
yeast-derived products, or any component of the product.
- mechanical ventilation before start of study
- patients with peripheral white blood cell count above 25.000 per microliter and/or
active myeloid malignancy
- patients on high dose systemic steroids (> 20 mg methylprednisolone or equivalent)
- patients on lithium carbonate therapy
- Patients enrolled in another investigational drug study
- Pregnant or breastfeeding females (all female subjects regardless of childbearing
potential status must have negative pregnancy test at screening)
- Patients with serum ferritin >2000 mcg/ml (which will exclude ongoing HLH)
AZ Sint Jan Brugge
Brugge, Belgium
University Hospital Ghent
Gent, Belgium
UZ Brussel
Jette, Belgium
AZ Delta Roeselare
Roeselare, Belgium
Bart Lambrecht, Principal Investigator
University Hospital, Ghent