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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04356690

Enrollment

Registered

2020-04-22

Start date

2020-05-08

Completion date

2022-07-01

Last updated

2023-06-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

COVID-19

Keywords

Etoposide, hemophagocytic lymphohistiocytosis (HLH), cytokine storm

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.

Interventions

DRUGEtoposide

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

SUPPORTIVE_CARE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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.

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)

Design outcomes

Primary

Measure	Time frame	Description
Improvement in Pulmonary Status by Two Categories on an 8 Point Ordinal Scale of Respiratory Function	baseline, through hospital discharge or death	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

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Cohort 1 - Etoposide Participants that are on ventilation Etoposide 150 mg/m2 daily days 1 and 4 Etoposide: Etoposide 150 mg/m2 administered intravenously once daily on Days 1 and 4.	6
Cohort 1 - Control Standard of care therapy in participants that are on ventilation	2
Total	8

Baseline characteristics

Characteristic	Cohort 1 - Control	Cohort 1 - Etoposide	Total
Age, Continuous	74.5 years	62.5 years	67 years
Baseline C Reactive protein levels	145.50 mg/L STANDARD_DEVIATION 111.02	151.17 mg/L STANDARD_DEVIATION 130.15	149.75 mg/L STANDARD_DEVIATION 117.76
Baseline d-dimer blood levels	4745.00 ng/ml DDU STANDARD_DEVIATION 6167.39	1394.00 ng/ml DDU STANDARD_DEVIATION 1183.31	2231.75 ng/ml DDU STANDARD_DEVIATION 2973.25
Baseline Ferritin Blood Levels	2699.5 ng/ml STANDARD_DEVIATION 3270.37	1754.17 ng/ml STANDARD_DEVIATION 797.34	1990.5 ng/ml STANDARD_DEVIATION 1474.28
Baseline platelet counts	274.50 cells x 1000 per mL STANDARD_DEVIATION 126.57	274.50 cells x 1000 per mL STANDARD_DEVIATION 193.45	274.50 cells x 1000 per mL STANDARD_DEVIATION 170.35
Baseline white blood cell counts	16.75 cells x1000 per mL STANDARD_DEVIATION 4.45	12.57 cells x1000 per mL STANDARD_DEVIATION 7.79	13.61 cells x1000 per mL STANDARD_DEVIATION 7.07
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	4 Participants	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1 Participants	2 Participants	3 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Asian	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized Black or African American	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized White	1 Participants	4 Participants	5 Participants
Region of Enrollment United States	2 participants	6 participants	8 participants
Sex: Female, Male Female	1 Participants	1 Participants	2 Participants
Sex: Female, Male Male	1 Participants	5 Participants	6 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	3 / 6	1 / 2
other Total, other adverse events	6 / 6	1 / 2
serious Total, serious adverse events	1 / 6	0 / 2

Outcome results

Primary

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

Time frame: baseline, through hospital discharge or death

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort 1 - Etoposide	Improvement in Pulmonary Status by Two Categories on an 8 Point Ordinal Scale of Respiratory Function	2 Participants
Cohort 1 - Control	Improvement in Pulmonary Status by Two Categories on an 8 Point Ordinal Scale of Respiratory Function	1 Participants

Secondary