This study is a randomized Double-Blind Placebo-Controlled Trial on the Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19
Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic caused by the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), and at present with no approved or proven
antiviral treatment.
Imatinib is a tyrosine kinase inhibitor that has been approved for treatment of many
hematologic and solid neoplasm. Imatinib is a weak base that compared to the extracellular
compartment is enriched over 1000-fold in the lysosome within several hours as a result of
its lysosomotropic property. Imatinib as a weak base accumulates in lysosomes resulting in
some antiviral activities by lysosomal alkalization required for virus/cell fusion.
Imatinib demonstrates in vitro activity against SARS-CoV viruses. Imatinib inhibit SARS-CoV
and MERS-CoV with micromolar EC50s (range, 9.8 to 17.6 μM) with low toxicity. The mechanism
of action studies suggested that ABL-1 tyrosine kinase regulates budding or release of
poxviruses and Ebola virus, demonstrating that the c-ABL-1 kinase signaling pathways play an
important role in the egress of these viruses. It is also reported that kinase signaling may
also be important for replication of two members of the Coronaviridae family, SARS-CoV and
MERS-CoV. In vivo studies performed in the mouse model of vaccinia virus infection showed
that imatinib was effective in blocking dissemination of the virus.
Imatinib has anti-inflammatory activity including its effectiveness in a "two-hit" murine
model of acute lung injury (ALI) caused by combined lipopolysaccharide (LPS) and
ventilator-induced lung injury (VILI). Imatinib significantly decreased bronchoalveolar
lavage protein, total cells, neutrophils, and TNFα levels in mice exposed to LPS plus VILI,
indicating that it attenuates ALI in this clinically relevant model. In another experiment,
imatinib attenuated ALI when given 4 hours after LPS, suggesting potential efficacy when
given after the onset of injury. Overall, these results strongly suggest the therapeutic
potential of imatinib against inflammatory vascular leak and a potential role of imatinib
combination therapy for patients with acute respiratory distress syndrome (ARDS) on
mechanical ventilation.
The investigators hypothesize that addition of imatinib to the best conventional care (BCC)
improves the outcome of hospitalized adult patients with COVID-19. This hypothesis is on the
bases of 1) intralysosomal entrapment of imatinib will increase endosomal pH and effectively
decrease SARS-CoV-2/cell fusion, 2) kinase inhibitory activity of imatinib will interfere
with budding/release or replication of SARS-CoV-2, and 3) because of the critical role of
mechanical ventilation in the care of patients with ARDS, imatinib will have a significant
clinical impact for patients with severe COVID-19 infection in Intensive Care Unit (ICU).
Drug: Imatinib
Therapeutic
Drug: Placebo oral tablet
Placebo
Inclusion Criteria
Patients may be included in the study only if they meet all of the following criteria:
1. Ability to understand and willingness to sign a written informed consent document.
Informed consent must be obtained prior to participation in the study. For patients
who are too unwell to provide consent such as patients on invasive ventilator or ECMO,
Legally Authorized Representative (LAR) can sign the informed consent.
2. Hospitalized patients ≥ 18 years of age
3. Positive RT-PCR assay for SARS-CoV-2 in the respiratory tract sample (oropharyngeal,
nasopharyngeal or BAL) by Center for Disease Control or local laboratory within 7 days
of randomization.
Exclusion Criteria
Patients meeting any of the following criteria are not eligible for the study:
1. Patients receiving any other investigational agents in a clinical trial. Off-label use
of agents such as hydroxychloroquine is not an exclusion criterion. Therapies that are
shown to be effective but may not be licensed can be added as an exception to the
exclusion criteria in order to allow for the most contemporary standard of care to
include emergency use authorization treatments as they become available. Antivirals
such as remdesivir will be permissible given the FDA authorized emergency use.
2. Pregnant or breastfeeding women.
3. Patients with significant liver or renal dysfunction function at screen as defined as:
- Direct bilirubin > 2.5 mg/dL
- AST, ALT, or alkaline phosphatase > 5 x upper limit of normal
- eGFR ≤ 30 mL/min or requiring renal replacement therapy
4. Patients with significant hematologic disorder at screen as defined as:
- Absolute neutrophil count (ANC) < 500/μL
- Platelet < 20,000/μL
- Hemoglobin < 7 g/dL
5. Uncontrolled undercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, uncontrolled active seizure
disorder, or psychiatric illness/social situations that per site Principal
Investigator's judgment would limit compliance with study requirements.
6. Known allergy to imatinib or its component products.
7. Any other clinical conditions that in the opinion of the investigator would make the
subject unsuitable for the study.
University of Maryland Medical Center
Baltimore, Maryland, United States