COVID-19
Conditions
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).
Interventions
DRUGImatinib
Therapeutic
DRUGPlacebo oral tablet
Placebo
Sponsors
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Arm A: Imatinib Arm B: Placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Efficacy and Safety of Oral Administration of Imatinib Combined With BCC vs. Placebo Plus BCC in Hospitalized Patients With COVID-19 | Day 28 after the start of imatinib/placebo. | The primary endpoint is all-cause mortality at Day 28 after the start of imatinib/placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-Cause Mortality | Day 29 to Day 60 after the start of imatinib/placebo | All-cause mortality post baseline |
| Time to a 2-point Clinical Change Using the 8-category Ordinal Scale. | Day 14 from baseline | The proportion of participants with two-point improvement at Day 14 from baseline using the 8-category ordinal scale. The ordinal scale is an evaluation of the 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. |
| Hospitalization | Up to 60 days post baseline | Duration of hospitalization |
| Duration of ECMO or Invasive Mechanical Ventilation | Up to 60 days post baseline | For subjects who are on ECMO or mechanical ventilation at Day 1 |
| Duration of ICU Stay | Up to 60 days post baseline | For subjects who are in ICU at Day 1 |
| Negative Oropharyngeal or Nasopharyngeal Swab | Day 14 | Proportion of patients with a negative oropharyngeal or nasopharyngeal swab for SARS-CoV-2 by quantitative RT PCR on days 14 and 28 |
| Serious Adverse Events (SAEs) | Up to 60 days post baseline | Percentage of subjects with serious adverse events |
| Discontinuation Due to Adverse Events | Up to 60 days post baseline | Percentage of subjects who discontinue study drug due to adverse events |
| Time to a 2-point Clinical Improvement Difference Over Baseline | Up to 60 days post baseline | Time to a 2-point clinical improvement difference over baseline |
Countries
United States
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 63 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 10 | 2 / 11 |
| other Total, other adverse events | 8 / 10 | 6 / 11 |
| serious Total, serious adverse events | 2 / 10 | 2 / 11 |
Outcome results
None listed