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Etoposide in Patients With COVID-19 Infection

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ClinicalTrials.gov Identifier: NCT04356690
Recruitment Status : Recruiting
First Posted : April 22, 2020
Last Update Posted : May 11, 2020
Sponsor:
Information provided by (Responsible Party):
Boston Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Etoposide Phase 2

Detailed Description:

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.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: A Phase II Single-Center, Randomized, Open-Label, Safety and Efficacy Study of Etoposide in Patients With COVID-19 Infection
Actual Study Start Date : May 8, 2020
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1 - Etoposide

Participants that are on ventilation Etoposide 150 mg/m2 daily days 1 and 4

If the treating clinicians feel that the patient initially benefited from etoposide but then has evidence of relapse of cytokine storm, the patient may continue on the standard HLH etoposide schedule of day 8, 11, 18, 25 after discussion with one of the study investigators.

Drug: Etoposide
Etoposide 150 mg/m2 administered intravenously once daily on Days 1 and 4. If the treating clinicians feel that the patient initially benefited from etoposide but then has evidence of relapse of cytokine storm, the patient may continue on the standard HLH etoposide schedule of day 8, 11, 18, 25 after discussion with one of the study investigators.
Other Name: Etopophos

Experimental: Cohort 2 - Etoposide

Participants that are NOT on ventilation Etoposide 150 mg/m2 daily days 1 and 4

Etoposide 150 mg/m2 administered intravenously once daily on Days 1 and 4. If the treating clinicians feel that the patient initially benefited from etoposide but then has evidence of relapse of cytokine storm, the patient may continue on the standard HLH etoposide schedule of day 8, 11, 18, 25 after discussion with one of the study investigators.

Drug: Etoposide
Etoposide 150 mg/m2 administered intravenously once daily on Days 1 and 4. If the treating clinicians feel that the patient initially benefited from etoposide but then has evidence of relapse of cytokine storm, the patient may continue on the standard HLH etoposide schedule of day 8, 11, 18, 25 after discussion with one of the study investigators.
Other Name: Etopophos

No Intervention: Cohort 1 - Control
Standard of care therapy in participants that are on ventilation
No Intervention: Cohort 2 - Control
Standard of care therapy in participants that are NOT on ventilation.



Primary Outcome Measures :
  1. Change in pulmonary status [ Time Frame: baseline, through study completion, an average of 45 days ]
    An 8 point ordinal scale will be used to assess pulmonary status consisting of the following values: 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= 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


Secondary Outcome Measures :
  1. Change in ferritin levels [ Time Frame: baseline, through study completion, an average of 45 days ]
  2. Change in C-reactive protein levels [ Time Frame: baseline, through study completion, an average of 45 days ]
  3. Change in d-dimer levels [ Time Frame: baseline, through study completion, an average of 45 days ]
  4. Change in white blood cell count [ Time Frame: baseline, through study completion, an average of 45 days ]
  5. Incidence of serious adverse events [ Time Frame: baseline, through study completion, an average of 45 days ]
    number of events

  6. Overall survival [ Time Frame: Days 15, 30 and 60 ]
  7. Length of hospitalization [ Time Frame: From date of enrollment until the date of extubation, assessed study completion, an average of 45 days ]
    When calculating days of hospitalization, re-hospitalization or death occurring in the first 28 days should result in zero ascribed to time out of the hospital prior to readmission.

  8. Duration of ventilation [ Time Frame: From date of enrollment until the date of extubation, assessed study completion, an average of 45 days ]
  9. Ventilator free days [ Time Frame: baseline, through study completion, an average of 45 days ]
    Reintubations or death within 28 days will result in zero ascribed time off ventilator prior to reintubation

  10. Improvement in arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) [ Time Frame: baseline, through study completion, an average of 45 days ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Cohort 2 (if activated): Evidence of progressive respiratory failure (requiring >4 L/min of supplemental oxygen to maintain oxygen saturation greater than 92%) without intubation;

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 vasopressors
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04356690


Contacts
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Contact: John Mark Sloan, MD 617-638-7002 mark.sloan@bmc.org
Contact: Sally A Fennessey, BS 617-638-8261 sally.fennessey@bmc.org

Locations
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United States, Massachusetts
Boston Medical Center Recruiting
Boston, Massachusetts, United States, 02118
Contact: Salli Fennessey    617-638-8261    sally.fennessey@bmc.org   
Principal Investigator: Mark Sloan, MD         
Sponsors and Collaborators
Boston Medical Center
Investigators
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Principal Investigator: John Mark Sloan, MD Boston Medical Center
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Responsible Party: Boston Medical Center
ClinicalTrials.gov Identifier: NCT04356690    
Other Study ID Numbers: H-40102
First Posted: April 22, 2020    Key Record Dates
Last Update Posted: May 11, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Boston Medical Center:
Etoposide
hemophagocytic lymphohistiocytosis (HLH)
cytokine storm
Additional relevant MeSH terms:
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Infection
Etoposide
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action