Etoposide in Patients With COVID-19 Infection

Study Overview
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Brief Summary
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This is a randomized, open-label phase II study designed to evaluate the safety and efficacy of etoposide in patients with the 2019 novel coronavirus (COVID-19) infection. Randomization will be performed with a 3:1 allocation ratio. Treatment will be comprised of etoposide administered intravenously at a dose of 150 mg/m2 on Days 1 and 4 in patients with COVID-19 infection meeting eligibility criteria. Subsequent doses of etoposide will be allowed if the investigator and treating physician believe the patient had clinical benefit from etoposide therapy but subsequently has evidence of recurrent clinical deterioration. Subjects randomized to control will receive standard of care treatment. No placebo will be used.

Detailed Description
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The rationale for the use of etoposide to treat the cytokine storm in COVID-19 is the high mortality associated with the hyperinflammatory response to the virus, which is similar to that seen in other secondary types of Hemophagocytic lymphohistiocytosis. Autopsy studies of Acute respiratory distress syndrome (ARDS) in COVID patients show a high number of cytolytic T cells in the lungs of such patients. Early autopsy results of COVID patients at Boston Medical Center demonstrate significant hemophagocytosis in lymph nodes and spleen. Comparable studies in the related coronavirus infection severe acute respiratory syndrome (SARS) have demonstrated hemophagocytosis, a hallmark of HLH.15 By targeting the T cells and monocytes driving the cytokine storm in patients with the more severe forms of COVID infection, we hope to alleviate the progression of lung and multi-organ dysfunction characteristic of patients who die from this illness.

Official Title
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A Phase II Single-Center, Randomized, Open-Label, Safety and Efficacy Study of Etoposide in Patients With COVID-19 Infection

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed COVID-19 infection Evidence of cytokine storm defined as: Peak ferritin > 10,000 ng/mL OR Peak ferritin > 500 ng/mL and one or more of the following at any time during hospital admission: Lactate dehydrogenase > 500 U/L, d-dimer >1000 ng/mL, C-reactive protein > 100 mg/L, or white blood count> 15 k/microlitre Cohort 1: Intubated status as a result of COVID infection-associated respiratory illness. Exclusion Criteria: Pregnancy or breastfeeding History of severe hypersensitivity to etoposide products Absolute neutrophil count (ANC) < 1000 cells/mm3 Platelet count <50,000/mm3 Bilirubin > 3.0 mg/dL Aspartate OR alanine aminotransferase > 5.0 x upper limit of normal Creatinine Clearance < 15 mL/min (calculated by Cockcroft Fault formula) Requiring continuous renal replacement therapy Requiring >1 vasopressor Requiring extracorporeal membrane oxygenation (ECMO) Other active, life-threatening infections Anti-cytokine treatment (including anakinra or Interleukin 6 antibodies eg tocilizumab, sarilumab) administration within three half-lives of the medication used Hydroxychloroquine, colchicine, azithromycin, doxycycline-if administered for COVID infection-must be discontinued for at least 24 hours prior to randomization. Has a history or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with subject participation, or is not in the best interest of the patient to participate, in the opinion of the investigator. Inability to consent and no legally authorized representative Poorly controlled HIV infection (CD4 count <100 cells/mm3)

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Etoposide<br>Participants that are on ventilation Etoposide 150 mg/m2 daily days 1 and 4 | Drug: Etoposide<br>* Etoposide 150 mg/m2 administered intravenously once daily on Days 1 and 4.<br>* Other names: Etopophos;|
| No Intervention: Cohort 1 - Control<br>Standard of care therapy in participants that are on ventilation | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in Pulmonary Status by Two Categories on an 8 Point Ordinal Scale of Respiratory Function | 8-Point Ordinal Scale of Respiratory Function: 8 -Death; 7 -Ventilation in addition to extracorporeal membrane oxygen (ECMO), continuous renal replacement therapy (CRRT), or need for vasopressors (dopamine ≥5 μg/kg/min OR epinephrine ≥0.1 μg/kg/min OR norepinephrine ≥0.1 μg/kg/min) 6 -Intubation and mechanical ventilation 5 -Non-invasive mechanical ventilation (NIV) or high-flow oxygen 4 -Hospitalized, requiring oxygen by mask or nasal prongs 3 -Hospitalization without oxygen supplementation 2-Discharged from hospital either to home with supplemental oxygen OR to inpatient rehabilitation/skilled nursing facility(+/-supplemental oxygen); 1 -Discharged to home without supplemental oxygen | baseline, through hospital discharge or death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Number of participants that lived to day 30 or hospital discharge | 30 Days | 
| Length of Hospitalization | Number of days participants were hospitalized after treatment | From date of enrollment until date of discharge | 
| Duration of Ventilation After Treatment | Number of days participants were ventilated after treatment | From date of enrollment until the date of extubation | 
| Change in Blood Ferritin Levels | Change in ferritin from treatment to day 30 | baseline, to day 30 (or discharge or death) | 
| Change in C-reactive Protein (CRP) Levels | Change in CRP levels from treatment to day 30 | baseline, to day 30 (or discharge or death) | 
| Change in D-dimer Blood Levels | Change in d-dimer from treatment to day 30 | baseline, to day 30 (or discharge or death) | 
| Change in White Blood Cell Count | Change in white blood cell count from treatment to day 30 | baseline, to day 30 (or discharge or death) | 
| Change in Platelet Count | Change in platelet count from treatment to day 30 | baseline, to day 30 (or discharge or death) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Etoposide, hemophagocytic lymphohistiocytosis (HLH), cytokine storm