Study of Sargramostim in Patients With COVID-19

Study Overview
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Brief Summary
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The purpose of this research is to find out if a drug (sargramostim) also known as Leukine® could help patient recover faster from COVID-19. Sargramostim may help the lungs recover from the effects of COVID-19, and this research study will help to find this out.

Detailed Description
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This Phase 2 study is designed as a proof of concept study and will randomize 2:1 approximately 120 patients with COVID-19 associated acute hypoxemia: of which 80 patients will receive sargramostim plus standard of care, and 40 patients who will receive standard of care alone. The aim of the study is to determine if inhaled sargramostim, as an adjunct to institutional standard of care, improves clinical outcomes in patients with COVID-19-associated acute hypoxemia. All patients on the sargramostim arm will be treated with 125 mcg inhaled sargramostim twice daily for 5 days, in addition to institutional standard of care. If required, upon progression to an invasive mechanical ventilator, administration of sargramostim may be delivered by intravenous infusion to complete a total of 5 days (including days delivered via inhalation). GM-CSF is a critical cytokine for healthy pulmonary function and is necessary for the maturation and maintenance of alveolar macrophages. Preclinical studies have shown GM-CSF confers resistance to influenza by enhancing innate immune mechanisms that depend on alveolar macrophages for their health and normal functioning. Clinical studies of sargramostim in patients with severe sepsis and respiratory dysfunction or acute respiratory distress syndrome have shown improvements in oxygenation and lung compliance.

Official Title
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A Phase 2 Trial Evaluating Sargramostim in Patients With COVID-19 Associated Acute Hypoxemia

Conditions
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COVID-19, SARS-CoV-2

Intervention / Treatment
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* Drug: Sargramostim
* Drug: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged ≥ 18 years Patients (or legally authorized decision maker) must provide informed consent Test positive for SARS-CoV-2 virus by PCR Admitted to hospital Presence of acute hypoxemia defined as (either or both) saturation below 93% on ≥ 2 L/min oxygen supplementation PaO2/FiO2 below 350 Exclusion Criteria: Patients requiring invasive (mechanical ventilation) or non-invasive (CPAP, BiPAP for hypoxemia) ventilation or ECMO (Note: oxygen supplementation using high flow oxygen systems or low flow oxygen systems would not exclude patients from this study) Intractable metabolic acidosis Cardiogenic pulmonary edema Hypotension requiring use of vasopressors Hyperferritinemia (serum ferritin ≥2,000 mcg/L) White blood cell count > 50,000/mm3 Participation in another interventional clinical trial for COVID-19 therapy Highly immunosuppressive therapy or anti-cancer combination chemotherapy within 24 hours prior to first dose of sargramostim Known or suspected intolerance or hypersensitivity to sargramostim, or any component of the product Previous experience of severe and unexplained side effects during aerosol delivery of any kind of medical product Presence of any preexisting illness that, in the opinion of the Investigator, would place the patient at an unreasonably increased risk through participation in this study Pregnant or breastfeeding females Severe or uncontrolled pulmonary comorbid conditions, including systemic steroid dependent asthma, systemic steroid dependent COPD, oxygen dependent COPD, lung transplant, known interstitial lung disease, or cystic fibrosis

Ages Eligible for Study
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Minimum Age: 18 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 Phase 2, randomized, open-label study will enroll approximately 120 patients with COVID-19 associated acute hypoxemia. It is a randomized 2:1 study to evaluate sargramostim treatment plus institutional standard of care compared to institutional standard of care alone.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sargramostim Arm<br>Day 1 - 5: Sargramostim treatment in addition to standard of care for COVID-19 | Drug: Sargramostim<br>* Sargramostim is a glycosylated, yeast-derived recombinant human granulocyte-macrophage colony stimulating factor (rhu-GM-CSF). Dosage for inhaled sargramostim: 125 mcg twice a day. Dosage for intravenous sargramostim: 125mcg/m2/day given over a 4 hour period.<br>* Other names: GM-CSF;Drug: Standard of care<br>* Standard of care for COVID-19<br>|
| Active Comparator: Control Arm<br>Standard of care for COVID-19 | Drug: Standard of care<br>* Standard of care for COVID-19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Oxygenation Parameter of P(A-a)O2 Gradient by Day 6 | The P(A-a)O2 gradient is a measure of how well the oxygen moves from the lungs into the bloodstream. Patients with a high gradient have less oxygen in the bloodstream. | 1-6 days | 
| Number of Patients Who Have Been Intubated by Day 14 |  | 1-14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ordinal Scale | The ordinal scale was used, where 0 is not hospitalized, no clinical or virological evidence of infection, and 8 is death. | 1-28 days | 
| All Cause 28-day Mortality |  | 1-28 days | 
| Number of Patients With Treatment-related Adverse Events | Number of patients with side effects related to treatment with sargramostim. Patients on the control arm did not receive sargramostim. | 1-58 days | 
| Survival Time of Patients |  | Day 1-90 | 
| Causes of Death |  | Day 1-90 | 
| Change From Baseline in P/F Ratio | The P/F ratio is a simple way to assess severity of low blood oxygen. It's the ratio of PaO2 (arterial oxygen partial pressure obtained from an arterial blood gas) to FiO2 (fraction of inspired oxygen expressed as a decimal). A normal arterial blood is gas 80 to 100 mm Hg. Normal room air has 21% or 0.21 oxygen. So a normal P/F ratio is about 380-475. A high P/F ratio means more oxygen in the bloodstream and a low P/F ratio means less oxygen in the bloodstream. This outcome measure compares the improvement (increase) in P/F ratio between treatment arms. | From Day 1 up to Day 6 | 
| Number of Participants Wtih Nosocomial Infections | Nosocomial infections also referred to as healthcare-associated infections (HAI), are infection(s) acquired during the process of receiving health care that was not present during the time of admission. | Day 1-90 | 
| Number of Patients Requiring Invasive Mechanical Ventilation | The is the number of patients that needed to be placed on a ventilator. | Day 1-90 | 
| Duration of Invasive, Non-invasive and Supplemental Oxygen | This endpoint includes duration of any/all types of respiratory support | Day 1-90 | 
| Duration of Hospitalization |  | Day 1-90 | 
| Time to Normalization of White Blood Cells and Lymphocytes | Normalization of WBC and lymphocyte count is defined as whether WBC and lymphocyte count results are normal or below normal or above normal ranges at available visits. | Day 1-90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, sargramostim, Leukine, rhu-GM-CSF, acute hypoxemia, iLeukPulm, SARS-CoV-2