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Etoposide in Patients With COVID-19 Infection

Primary Purpose

COVID-19

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Etoposide

About this trial

This is an interventional supportive care trial for COVID-19 focused on measuring Etoposide, hemophagocytic lymphohistiocytosis (HLH), cytokine storm

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Boston Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Cohort 1 - Etoposide

Cohort 1 - Control

Arm Description

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

Standard of care therapy in participants that are on ventilation

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Overall Survival

Number of participants that lived to day 30 or hospital discharge

Length of Hospitalization

Number of days participants were hospitalized after treatment

Duration of Ventilation After Treatment

Number of days participants were ventilated after treatment

Change in Blood Ferritin Levels

Change in ferritin from treatment to day 30

Change in C-reactive Protein (CRP) Levels

Change in CRP levels from treatment to day 30

Change in D-dimer Blood Levels

Change in d-dimer from treatment to day 30

Change in White Blood Cell Count

Change in white blood cell count from treatment to day 30

Change in Platelet Count

Change in platelet count from treatment to day 30

Full Information

NCT ID

NCT04356690

First Posted

April 17, 2020

Last Updated

May 22, 2023

Sponsor

Boston Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT04356690

Brief Title

Etoposide in Patients With COVID-19 Infection

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Terminated

Why Stopped

Slow accrual, change in COVID prevalence, availability of effective vaccine

Study Start Date

May 8, 2020 (Actual)

Primary Completion Date

July 1, 2022 (Actual)

Study Completion Date

July 1, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Boston Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

COVID-19

Keywords

Etoposide, hemophagocytic lymphohistiocytosis (HLH), cytokine storm

7. Study Design

Primary Purpose

Supportive Care

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1 - Etoposide

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 1 - Control

Arm Type

No Intervention

Arm Description

Standard of care therapy in participants that are on ventilation

Intervention Type

Drug

Intervention Name(s)

Etoposide

Other Intervention Name(s)

Etopophos

Intervention Description

Etoposide 150 mg/m2 administered intravenously once daily on Days 1 and 4.

Primary Outcome Measure Information:

Title

Improvement in Pulmonary Status by Two Categories on an 8 Point Ordinal Scale of Respiratory Function

Description

Time Frame

baseline, through hospital discharge or death

Secondary Outcome Measure Information:

Title

Overall Survival

Description

Number of participants that lived to day 30 or hospital discharge

Time Frame

30 Days

Title

Length of Hospitalization

Description

Number of days participants were hospitalized after treatment

Time Frame

From date of enrollment until date of discharge

Title

Duration of Ventilation After Treatment

Description

Number of days participants were ventilated after treatment

Time Frame

From date of enrollment until the date of extubation

Title

Change in Blood Ferritin Levels

Description

Change in ferritin from treatment to day 30

Time Frame