Clinical trial NCT04394416: Trial of Imatinib for Hospitalized Adults With COVID-19
Official title: Randomized Double-Blind Placebo-Controlled Trial on the Safety and Efficacy of Imatinib for Hospitalized Adults With COVID-19
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: COVID-19
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
First posted: 2020-05-19
Enrollment: 204
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Arm A: Imatinib

Arm B: Placebo
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: The proportion of patients with a two-point change using the 8-category ordinal scale
timeFrame: Day 14 from baseline
Secondary outcomes:
measure: All-Cause mortality
timeFrame: Day 28 and Day 60 post baseline
measure: Time to a 2-point clinical change
timeFrame: Up to 60 days post baseline
measure: Hospitalization
timeFrame: Up to 60 days post baseline
measure: Duration of ECMO or invasive mechanical ventilation
timeFrame: Up to 60 days post baseline
measure: Duration of ICU stay
timeFrame: Up to 60 days post baseline
measure: SARS-CoV-2 negative
timeFrame: Up to 60 days post baseline
measure: Negative oropharyngeal or nasopharyngeal swab
timeFrame: Up to 28 days post baseline
measure: Serious adverse events (SAEs)
timeFrame: Up to 60 days post baseline
measure: Discontinuation due to adverse events
timeFrame: Up to 60 days post baseline
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
Study officials:
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