Trial of Imatinib for Hospitalized Adults With COVID-19

Study Overview
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Brief Summary
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This study is a randomized Double-Blind Placebo-Controlled Trial on the Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19

Detailed Description
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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).

Official Title
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Randomized Double-Blind Placebo-Controlled Trial on the Safety and Efficacy of Imatinib for Hospitalized Adults With COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Imatinib
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients may be included in the study only if they meet all of the following criteria: 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. Hospitalized patients ≥ 18 years of age 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: 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. Pregnant or breastfeeding women. 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 Patients with significant hematologic disorder at screen as defined as: Absolute neutrophil count (ANC) < 500/μL Platelet < 20,000/μL Hemoglobin < 7 g/dL 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. Known allergy to imatinib or its component products. Any other clinical conditions that in the opinion of the investigator would make the subject unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arm A: Imatinib Arm B: Placebo
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imatinib<br>Imatinib oral 400 mg daily for 14 days. | Drug: Imatinib<br>* Therapeutic<br>|
| Active Comparator: Placebo<br>Placebo oral for 14 days | Drug: Placebo oral tablet<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with a two-point change using the 8-category ordinal scale | The ordinal scale is an evaluation of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death. | Day 14 from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-Cause mortality | All-cause mortality post baseline | Day 28 and Day 60 post baseline | 
| Time to a 2-point clinical change | Time to a 2-point clinical change difference | Up to 60 days post baseline | 
| Hospitalization | Duration of hospitalization | Up to 60 days post baseline | 
| Duration of ECMO or invasive mechanical ventilation | For subjects who are on ECMO or mechanical ventilation at Day 1 | Up to 60 days post baseline | 
| Duration of ICU stay | For subjects who are in ICU at Day 1 | Up to 60 days post baseline | 
| SARS-CoV-2 negative | Time to SARS-CoV-2 negative by reverse transcriptase-polymerase chain reaction (RT-PCR) | Up to 60 days post baseline | 
| Negative oropharyngeal or nasopharyngeal swab | Proportion of patients with negative oropharyngeal or nasopharyngeal swab for SARS-CoV-2 by quantitative RT PCR on days 5, 10, 14, 21, and 28 after starting treatment | Up to 28 days post baseline | 
| Serious adverse events (SAEs) | Proportion of subjects with serious adverse events | Up to 60 days post baseline | 
| Discontinuation due to adverse events | Proportion of subjects who discontinue study drug due to adverse events | Up to 60 days post baseline |