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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Prospective, Randomized, Open-label, Interventional Study to Investigate the Efficacy of Sargramostim (Leukine®) in Improving Oxygenation and Short- and Long-term Outcome of COVID-19 (Corona Virus Disease) Patients With Acute Hypoxic Respiratory Failure.

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Sargramostim
* Other: Control


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active sargramostim treatment group<br>Inhaled sargramostim 125mcg twice daily for 5 days on top of standard of care. Upon progression to ARDS and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125mcg/m2 body surface area once daily 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 | Drug: Sargramostim<br>* Inhalation via mesh nebulizer and/or IV administration upon Clinical deterioration<br>* Other names: LEUKINE;|
| Placebo Comparator: Control group<br>standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards, will have the option (clinician's decision) to initiate IV sargramostim 125mcg/m2 body surface area once daily for 5 days | Drug: Sargramostim<br>* Inhalation via mesh nebulizer and/or IV administration upon Clinical deterioration<br>* Other names: LEUKINE;Other: Control<br>* Standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in Oxygenation | Mean Change from Baseline in PaO2/FiO2 on Day 6 or hospital discharge, whichever came first | on Day 6 or hospital discharge, whichever came first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in 6-point Ordinal Scale for Clinical Improvement | The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO (Extracorporeal Membrane Oxygenation) ; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome | at Baseline, at Day 6 | 
| Number of Days in Hospital |  | through study completion, an average of 5 months | 
| Number of Participants With Nosocomial Infection no./Total no (%) |  | during hospital admission (up to 28 days) | 
| Death |  | at 28 days | 
| Number of Participants Progressed to Mechanical Ventilation and/or ARDS |  | during hospital admission (up to 28 days) | 
| Time to Clinical Sign Score < 6 for at Least 24h | Clinical Sign score (0-18) by scoring 6 clinical signs from 0 to 3 (0 = absent, 1 = mild, 2 = moderate and 3 = severe): Fever (0 = <37°C; 1 = 37.1-38°C; 2 = 38.1-39°C; 3 = >39°C) last 24h; Cough; Fatigue; Shortness of breath; Diarrhea; Body pain. Higher values represent a worse outcome | During hospital admission (up to 28 days) | 
| Change in Clinical Sign Score | Clinical Sign score (0-18) by scoring 6 clinical signs from 0 to 3 (0 = absent, 1 = mild, 2 = moderate and 3 = severe): Fever (0 = <37°C; 1 = 37.1-38°C; 2 = 38.1-39°C; 3 = >39°C) last 24h; Cough; Fatigue; Shortness of breath; Diarrhea; Body pain. Higher values represent a worse outcome. | at baseline, at day 6 | 
| Change in (National Early Warning Score2) NEWS2 Score | The NEWS2 score standardises the assessment and response to acute illness. Six physiological parameters form the basis of the scoring system: respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new confusion, temperature. The total possible score ranges from 0 to 20. The higher the score the greater the clinical risk | at baseline, at day 6 | 
| Change in Sequential Organ Failure Assessment (SOFA Score) | The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems (respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Score ranges from 0 (best) to 24 (worst) points. | at baseline, at day 6 | 
| Change in Ferritin Level |  | at baseline, at day 6 | 
| Change in D-dimer Level |  | at baseline, at day 6 | 
| Change in CRP Level |  | at baseline, at day 6 | 
| Change in Lymphocyte Count |  | at baseline, at day 6 | 
| Change in Eosinophil Count |  | at baseline, at day 6 | 
| HRCT (High-Resolution Computed Tomography) Fibrosis Score | The HRCT fibrosis score is a subjective assessment of the overall extent of normal attenuation, reticular abnormalities, honeycombing and traction bronchiectasis . The HRCT findings are graded on a scale of 1-4 based on the classification system: 1. normal attenuation; 2. reticular abnormality; 3. traction bronchiectasis; and 4. honeycombing. The presence of each of the above four HRCT findings is assessed independently in three (upper, middle and lower) zones of each lung. The extent of each HRCT finding was determined by visually estimating the percentage (to the nearest 5%) of parenchymal involvement in each zone. The score for each zone was calculated by multiplying the percentage of the area by the grading scale score (i.e. 1. normal attenuation; 2. reticular abnormality; 3. traction bronchiectasis; and 4. honeycombing). The six zone scores were averaged to determine the total score for each patient. The score ranges from 100 to 400, higher values represent more fibrosis. | at follow-up, 10-20 weeks after day 10 or discharge, whichever comes first | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GM-CSF, Acute Lung Injury, Hypoxia, Acute Respiratory Distress Syndrome, Corona virus, COVID-19, SARS (Severe Acute Respiratory Syndrome), Alveolar Macrophage, Acute Hypoxic respiratory failure