Sargramostim in Patients With Acute Hypoxic Respiratory Failure Due to COVID-19 (SARPAC)

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.

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)