Etoposide in Patients With COVID-19 Infection

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

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.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Drug: Etoposide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Boston Medical Center
• Investigators: Principal Investigator: John Mark Sloan, MD, Boston Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2020
• Primary Completion (Actual): July 1, 2022
• Study Completion (Actual): July 1, 2022

Study Registration Dates

• First Submitted: April 17, 2020
• First Submitted That Met QC Criteria: April 20, 2020
• First Posted (Actual): April 22, 2020

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: May 22, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Etoposide; hemophagocytic lymphohistiocytosis (HLH); cytokine storm
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Etoposide
• Other Study ID Numbers: H-40102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No