Etoposide in Patients With COVID-19 Infection

• ClinicalTrials.gov Identifier: NCT04356690
• Recruitment Status: Recruiting
• First Posted: April 22, 2020
• Last Update Posted: January 5, 2021
• Sponsor: Boston Medical Center
• Information provided by (Responsible Party): Boston Medical Center

Study Description

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.

Study Design

• 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 2021
• Estimated Study Completion Date: June 2022

Arms and Interventions

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.

Outcome Measures

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 ]

Eligibility Criteria

• 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)

Contacts and Locations

Contacts

Contact: John Mark Sloan, MD; 617-638-7002; mark.sloan@bmc.org

Contact: Annie A Jose, BS; 617-638-8213; annie.jose@bmc.org

Locations

United States, Massachusetts

Boston Medical Center; Recruiting

Boston, Massachusetts, United States, 02118

Contact: Annie Jose, BS 617-638-8213 annie.jose@bmc.org

Principal Investigator: Mark Sloan, MD

Sponsors and Collaborators

Boston Medical Center

Investigators

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

More Information

• Responsible Party: Boston Medical Center
• ClinicalTrials.gov Identifier: NCT04356690
• Other Study ID Numbers: H-40102
• First Posted: April 22, 2020
• Last Update Posted: January 5, 2021
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Infection; Etoposide; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action