Using GM-CSF as a Host Directed Therapeutic Against COVID-19

Study Overview
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Brief Summary
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The coronavirus disease 2019 (COVID-19) has rapidly become a pandemic. COVID-19 poses a mortality risk of 3-7%, rising to 20% in older patients with co-morbidities. Of all infected patients, 15-20% will develop severe respiratory symptoms necessitating hospital admission. Around 5% of patients will require invasive mechanical ventilation, and up to 50% will die. Evidence in severe COVID-19 suggests that these patients experience cytokine storm and progressed rapidly with acute respiratory distress syndrome and eventual multi-organ failure. Early identification and immediate treatment of hyperinflammation is thus recommended to reduce mortality. Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) has been shown to be a myelopoietic growth factor that has pleiotropic effects in promoting the differentiation of immature precursors into polymorphonuclear neutrophils, monocytes/ macrophages and dendritic cells, and also in controlling the function of fully mature myeloid cells. It plays an important role in priming monocytes for production of proinflammatory cytokines under TLR and NLR stimulation. It has a broad impact on the processes driving DC differentiation and affects DC effector function at the mature state. Importantly, GM-CSF plays a critical role in host defense and stimulating antiviral immunity. Detailed studies have also shown that GM-CSF is necessary for the maturation of alveolar macrophages from foetal monocytes and the maintenance of these cells in adulthood. The known toxicology, pharmacologic and safety data also support the use of Leukine® in hypoxic respiratory failure and ARDS due to COVID-19. This study aims to recruit patients with evidence of pneumonia and hypoxia who have increased risk for severe disease and need for mechanical ventilation. The overall hypothesis is that GM-CSF has antiviral immunity, can provide the stimulus to restore immune homeostasis in the lung with acute lung injury from COVID-19, and can promote lung repair mechanisms, which would lead to improvement in lung oxygenation parameters.

Detailed Description
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The hypothesis of the proposed intervention is that GM-CSF has profound effects on antiviral immunity, can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post COVID-19, and can promote lung repair mechanisms, which would lead to an improvement in lung oxygenation parameters. This hypothesis is based on experiments performed in mice showing that GM-CSF treatment can prevent mortality and prevent ARDS in mice with post-viral acute lung injury. In the interim analysis of the SARPAC trial, patients who received nebulised Leukine® via a mesh inhaler showed a trend in improvement in their P(A-a)O2 gradient at day 6 compared to the SOC group. There are however, anticipated logistical difficulties of training and infection control concerns with administering of nebulised Leukine® via a specialised inhaler in the negative pressure room. Hence we propose to randomize patients with confirmed COVID-19 and acute hypoxic respiratory failure (saturation < 94% on room air or PaO2/FiO2 <350) to receive iv Leukine® 125mcg/m2 once a day for 5 days on top of SOC (treatment group A), or to receive SOC treatment only (placebo group B). Dosing of systemic Leukine® is based on prior experience of using this drug in patients with pneumonia-associated ARDS. To measure the effectiveness of Leukine® in restoring lung homeostasis, the primary endpoint of this intervention is measuring oxygenation after 5 days of intravenous treatment through assessment of pre-treatment and post-treatment ratio of PaO2/FiO2, and through measurement of the P(A-a)O2 gradient, which can easily be performed in the setting of clinical observation of inpatients. During the 5-day treatment period, we will perform daily measurements of oxygen saturation (pulse oximetry) in relation to FiO2, and the slope of alterations in these parameters could also be an indicator that our hypothesis is correct. Comparison will be between group A receiving iv Leukine® on top of standard of care (SOC) and placebo group B receiving SOC only. Data from the Wuhan COVID-19 epidemic show that patients that deteriorate are facing a prolonged period of mechanical ventilation. Therefore, the study will be unblinded at day 5, or at any time within the first 5 days of study should the patient deteriorate clinically with need for supplemental oxygen FiO2 requirement ≥ 0.5. Patients in group B will then have the option to receive 5 days of iv Leukine®, based on the treating physician's assessment. This group will be group D. Patients who require mechanical ventilation also have the option to receive an additional 5 days of iv Leukine®, based on the treating physician's assessment (group C and E). A total of 30 patients with confirmed COVID-19 and acute hypoxic respiratory failure will be enrolled, 15 who will receive Leukine® + SOC, and 15 who will receive placebo + SOC. The target group of subjects is defined as confirmed COVID-19 patients with acute hypoxic respiratory failure admitted to the COVID-19 isolation ward. Subjects will be recruited from the isolation wards located in Singapore General Hospital (SGH). Subjects will be identified by the primary managing physicians who are infectious diseases physicians. 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, triglyceride levels, etc. as well as occurrence of secondary bacterial infections. Patients will stop the investigational drug if there is unacceptable toxicity according to investigator's judgement.

Official Title
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Using GM-CSF as a Host Directed Therapeutic Against COVID-19 - a Phase 2 Investigator Initiated Trial

Conditions
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COVID, Sars-CoV2, ARDS, Human

Intervention / Treatment
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* Drug: Sargramostim
* Other: Normal Saline 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SARS-CoV-2 PCR-confirmed COVID-19 infection Presence of acute hypoxic respiratory failure defined as (either or both) Saturation < 94% on room air or requiring supplemental oxygen PaO2/FiO2 below 350 Age 21-80 Able and willing to provide informed consent Exclusion Criteria: Patients who are already on supplemental oxygen of FiO2 ≥ 0.4 Patients with known history of serious allergic reactions, including anaphylaxis, to human GM-CSF such as Leukine®, yeast-derived products, or any component of the product. Mechanical ventilation before start of study Patients enrolled in another investigational drug study Pregnant or breastfeeding females (all female subjects of childbearing potential status must have negative pregnancy test at screening) Patients with peripheral white blood cell count above 25,000 per microliter and/or active myeloid malignancy Patients on high dose systemic steroids (> 20mg methylprednisolone or equivalent) Patients on lithium carbonate therapy Patients with serum ferritin >2000 mcg/ml (which will exclude ongoing HLH)

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized, double-blind, placebo-controlled clinical trial of iv Leukine® in 30 patients with confirmed COVID-19 and acute hypoxic respiratory failure.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Treatment Group<br>Day 1 - 5: Receive study medication Leukine® 125mcg/m2 body surface area daily (via infusion into the vein) in addition to standard of care treatments | Drug: Sargramostim<br>* Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.<br>* Other names: Leukine®;|
| Placebo Comparator: Group B: Placebo Group<br>Day 1 - 5: Receive normal saline 0.9% daily (via infusion into the vein) in addition to standard of care treatments | Other: Normal Saline 0.9%<br>* IV normal saline 0.9% for 5 days<br>|
| Experimental: Group C<br>Day 6 - 10: Subjects in Group A who require mechanical ventilation to receive an additional 5 days of IV Leukine® 125mcg/m2 body surface area daily, in addition to standard of care treatments (based on the treating physician's assessment) | Drug: Sargramostim<br>* Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.<br>* Other names: Leukine®;|
| Experimental: Group D<br>Day 6 - 10: Subjects from Group B to receive study medication (based on the treating physician's assessment), Leukine® 125mcg/m2 body surface area daily (via infusion into the vein) in addition to standard of care treatments | Drug: Sargramostim<br>* Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.<br>* Other names: Leukine®;|
| Experimental: Group E<br>Day 11 - 15: Subjects in Group D who require mechanical ventilation to receive an additional 5 days of IV Leukine® 125mcg/m2 body surface area daily, in addition to standard of care treatments (based on the treating physician's assessment) | Drug: Sargramostim<br>* Dosage for IV Leukine® injection: 125mcg/m2/day over a 4-hour period for up to 5 days.<br>* Other names: Leukine®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measuring oxygenation | To measure the effectiveness of Leukine® in restoring lung homeostasis, the primary endpoint of this intervention is measuring oxygenation after 5 days of intravenous treatment through assessment of pre-treatment and post-treatment ratio of PaO2/FiO2, and through measurement of the P(A-a)O2 gradient, which can easily be performed in the setting of clinical observation of inpatients. | Day 1 to Day 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pandemic, host-directed therapeutic, GM-CSF, COVID-19, ARDS, SARS-CoV2