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.
Drug: Etoposide
Etoposide 150 mg/m2 administered intravenously once daily on Days 1 and 4.
Other Name: Etopophos
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)
Boston Medical Center
Boston, Massachusetts, United States
John Mark Sloan, MD, Principal Investigator
Boston Medical Center