Clinical trial NCT04356690: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: COVID-19
Keywords: Etoposide
hemophagocytic lymphohistiocytosis (HLH)
cytokine storm
Lead sponsor: Boston Medical Center
Sponsor class: OTHER
First posted: 2020-04-22
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility 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.

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)

Primary outcomes:
measure: Improvement in Pulmonary Status by Two Categories on an 8 Point Ordinal Scale of Respiratory Function
timeFrame: baseline, through hospital discharge or death
Secondary outcomes:
measure: Overall Survival
timeFrame: 30 Days
measure: Length of Hospitalization
timeFrame: From date of enrollment until date of discharge
measure: Duration of Ventilation After Treatment
timeFrame: From date of enrollment until the date of extubation
measure: Change in Blood Ferritin Levels
timeFrame: baseline, to day 30 (or discharge or death)
measure: Change in C-reactive Protein (CRP) Levels
timeFrame: baseline, to day 30 (or discharge or death)
measure: Change in D-dimer Blood Levels
timeFrame: baseline, to day 30 (or discharge or death)
measure: Change in White Blood Cell Count
timeFrame: baseline, to day 30 (or discharge or death)
measure: Change in Platelet Count
timeFrame: baseline, to day 30 (or discharge or death)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
Study officials:
affiliation: Boston Medical Center
name: John Mark Sloan, MD
role: PRINCIPAL_INVESTIGATOR
References: