This study is a randomized Double-Blind Placebo-Controlled Trial on the Safety andEfficacy 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