Randomized Double-Blind Placebo-Controlled Trial on the Safety and Efficacy of Imatinib for Hospitalized Adults With COVID-19
Phase: PHASE3
Conditions: COVID-19
Sponsor: University of Maryland, Baltimore

1 
 
Randomized Double-Blind Placebo-Controlled Trial on the 
Safety and Efficacy of Imatinib for Hospitalized Adults with 
COVID-19 
 
Investigational Agent: Imatinib 
 
Protocol Number: 2038GCCC 
HRPO Number: HP-00090890 
IND: 149239 
NCT: 04394416 
 
Sponsor: 
Andrea R. Levine, M.D., M.S. 
 
Protocol Version: 3 
January 31, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
The information contained in this protocol is confidential and is intended for the use of the clinical 
investigators and their study staff. The information in this document is the property of University 
of Maryland Baltimore, and may not be disclosed unless federal or state law or regulations require 
such disclosure. This information may be disclosed only to those persons involved in the study 
who have a need to know, with the obligation not to further disseminate this information. 
 

2 
 
Key Personnel 
Principal Investigator:  
 
Andrea R. Levine, M.D., M.S. 
Assistant Professor of Medicine 
University of Maryland School of Medicine 
Division of Pulmonary & Critical Care Medicine  
419 West Redwood Street, Suite 600 
Baltimore, MD 21201 
Telephone: 410-328-8141 
Fax: 410-328-0177 
E-mail: andrea.levine@som.umaryland.edu  
 
Co-Investigator: 
 
Joel V. Chua, M.D. 
Assistant Professor of Medicine 
Chief, Surgical Infectious Disease, UMMC 
University of Maryland School of Medicine, Institute of Human Virology 
725 West Lombard Street, Room N146 
Baltimore, MD 21201 
Telephone: 410-706-5704 
Fax: 410-706-3243 
Email: jchua@ihv.umaryland.edu 
  
Rohit Talwani, M.D. 
Associate Professor of Medicine 
University of Maryland School of Medicine, Institute of Human Virology 
725 West Lombard Street 
Baltimore, MD 21201 
Telephone: 410-706-8264 
Fax: 410-706-4619 
E-mail: rtalwani@ihv.umaryland.edu 
 
Nirav G. Shah, M.D. 
Associate Professor of Medicine 
University of Maryland School of Medicine 
Division of Pulmonary & Critical Care Medicine  
419 West Redwood Street, Suite 600 
Baltimore, MD 21201 
Telephone: 410-328-8141 
Fax: 410-328-0177 
E-mail: Andrea. ngshah@som.umaryland.edu 
 
Statistician: Søren Bentzen, Ph.D., D.Sc. 
 
Lead Protocol Coordinator: Larissa Sanglard , Email: Larissa.Sanglard@umm.edu 
  

3 
 
Protocol Synopsis 
 
Title: Randomized Double-Blind, Placebo-Controlled Trial on the Safety and Efficacy of 
Imatinib for Hospitalized Adults with COVID-19. 
Study Phase: 3 
Background and Rationale:  
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 limited proven treatment. 
Imatinib is a tyrosine kinase inhibitor that has been approved for treatment of many hematologic 
and solid neoplasms. 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. Accumulation of imatinib as a weak base in lysosomes may result in some antiviral 
activities by lysosomal alkalization required for virus/cell fusion. 
Imatinib demonstrated in vitro activity against SARS-CoV viruses. Imatinib inhibits 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 therapy for patients with acute respiratory distress syndrome 
(ARDS) on mechanical ventilation. 
We hypothesized 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). 
Target Population:  
Hospitalized adult patients with COVID-19 
Hypothesis: 
Addition of imatinib to the BCC will provide a superior clinical outcome for patients with 
COVID-19 compared with BCC plus placebo   
Primary Objectives 
To evaluate the efficacy, safety, and tolerability of imatinib compared with placebo in 
combination with the BCC in adults hospitalized with COVID-19 

4 
 
Primary Endpoint 
The primary endpoint is all-cause mortality at Day 28 after the start of imatinib/placebo.  
Secondary Endpoints 
 All-cause mortality at Day 60 after the start of imatinib/placebo 
 The proportion of patients with a two-point improvement at Day 14 from baseline 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 
 Time to a 2-point clinical improvement difference over baseline 
 Duration of hospitalization 
 Duration of ECMO or invasive mechanical ventilation (for participants who are on ECMO 
or mechanical ventilation at Day 1) 
 Duration of ICU stay (for participants who are in ICU at Day 1)  
 Proportion of participants with negative oropharyngeal or nasopharyngeal swab for SARS-
CoV-2 by quantitative RT-PCR on days 14 and 28 after starting treatment 
 Proportion of participants with serious adverse events 
 Proportion of participants who discontinue study drug due to adverse events 
Study design 
 This is an individual patient-level randomized, double-blind, placebo-controlled phase 3 
study to evaluate the safety and efficacy of imatinib for the treatment of hospitalized 
adults with COVID-19. Participants will be followed for up to 60 days from start of study 
drug administration. Eligible patients will be randomized in 2:1 (imatinib/placebo) ratio 
to receive either imatinib or placebo for 14 days. Both groups will receive the best 
conventional care (BCC, detailed in Section 1.6).  
 In order to balance the severity of the respiratory illness between the two arms, per FDA 
recommendation randomization will be stratified based on radiographic findings and 
oxygen requirements:  
1) Severe disease: evidence of pneumonia on chest X-ray or CT scan or chest 
auscultation (rales, crackles), and SpO2 ≤ 92% on ambient air or PaO2/FiO2 < 300 
mmHg, and requires supplemental oxygen administration by nasal cannula, simple 
face mask, or other similar oxygen delivery device  
2) Critical disease: requires supplemental oxygen delivered by non-rebreather mask or 
high flow cannula or use of invasive or non-invasive ventilation or requiring 
treatment in an ICU, use of vasopressors, or extracorporeal life support. 
 This trial will be conducted in accordance with the principles of the Declaration of 
Helsinki and the Good Clinical Practice guidelines of the International Conference on 
Harmonization. 
 

5 
 
Sample Size  
The trial is designed as a double-blind, two-parallel arm, randomized controlled study with a 1:1 
allocation ratio to: Arm A) imatinib or Arm B) placebo. Patients in both arms will receive the best 
conventional care (BCC) per local institutional standards at the discretion of the treating 
physician. 
Group sample sizes of 173 in Arm A and 173 in Arm B achieve 80% power to detect a difference 
between the mortality in the two trial arms of 0.10. The proportion in Arm A (imatinib treatment 
arm) is assumed to be 0.10 under the null hypothesis and 0.20 under the alternative hypothesis. 
The proportion in Arm B (placebo control arm) is 0.10. The test statistic used is the one-sided 
Fisher's Exact Test. The significance level of the test is targeted at 0.05. The significance level 
actually achieved by this design is α=0.0385. The power of the test is calculated using binomial 
enumeration of all possible outcomes.  
The primary analysis will be conducted using an intention to treat principle (ITT) for participants 
who at least receive one dose of study drug or placebo. The sample size is not inflated for 
dropouts. All patients will be evaluable irrespective of the clinical course of their disease. 
Key Eligibility Criteria  
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 outside 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, remdesivir, or immunomodulators is not an exclusion 
criterion. 
 Pregnant or breastfeeding women 
 Patients with significant liver dysfunction function at screen as defined as: 
o Total bilirubin > 2.5 mg/dL 
o ALT > 5 x upper limit of normal 
 Patients with significant hematologic disorder at screen as defined as:  
o Absolute neutrophil count (ANC) < 200/µL 
o Platelet < 20,000/µL 
o 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 
participant unsuitable for the study 

6 
 
Study Treatments: Imatinib oral 400 mg daily or placebo for 14 days 
 
Study Centers: University of Maryland Medical Center (UMMC), Baltimore, MD is the 
initiating site. The study may be opened in up to 15 more centers including but not limited to 
University of Maryland Medical System (UMMS) hospitals across the United States and other 
countries on the bases of the accrual rate or the magnitude of COVID-19 pandemic.  
We are aware of the enrollment requirement of ~350 patients, which is required to provide 
scientific integrity of the results. We are also aware of the fact that enrolling this number of 
patients in a single-site at UMMC may take longer than expected particularly taken into account 
other competing studies. For this reason, we actively consider to open the study in other sites. 
After identification of other sites, we will fulfill all regulatory requirements before enrolling 
patients in other sites. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

7 
 
Schedule of Activities 
 
ASSESSMENTS/ 
OBSERVATIONS 
Screen   
(D-3 to 
D1) 
Day 
1
Day 
2
Day 
5
Day 
8
Day 
10
Day 
14a
Day 
21j 
Day 
28j 
Day 
60b,j
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±7 d 
±7 d 
±7 d 
Informed consent
X 
  
  
  
  
  
  
  
  
  
Confirm eligibility
X 
X 
  
  
  
  
  
  
  
  
Randomization
  
X 
  
  
  
  
  
  
  
  
Study drug administrationc
  
X 
  
  
  
Demographics
X
Medical history
X 
  
  
  
  
  
  
  
  
  
Vital signs & Physical examd
X 
X 
  
X 
  
X 
X 
 X 
X  
 X 
Clinical assessmentse                
X 
X 
CBC with differential count
X 
  
X 
X 
  
X 
X 
  
X 
X 
Chemistriesf,g
X 
  
X 
X 
  
X 
X 
  
X 
X  
CRPg 
X 
  
  
X 
  
  
X 
  
X 
 X 
ECG
X 
  
  
  
  
  
  
  
  
  
Pregnancy test
X 
  
  
  
  
  
  
  
  
  
Targeted AE assessment
  
X 
Concomitant medication
X 
X 
  
X 
  
X 
X 
X  
X  
 X 
Primary endpoint assessment
  
  
  
  
  
  
X 
  
  
  
SARS-CoV-2 PCRh,i
X  
X 
  
X 
  
X 
X 
  
X 
  
Correlative/scientific studiesi 
  
X 
  
  
X 
  
X 
  
Screen (Day -3 to Day 1) - Screening and Day 1 visits can occur the same day.
a Early discharge visit - use Day 14 assessments
b Early termination visit - use Day 60 assessments 
c For planned 14 days
 
 
 
 
 
 
 
 
d Clinically appropriate physical exams including vital signs and O2 saturation
e Clinical assessments: 8-point ordinal scale and respiratory treatment status. Daily while hospitalized.
f Chemistries  include the following: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, 
magnesium, phosphorous, AST, ALT, total bilirubin, alkaline phosphatase, albumin, total protein, and LDH. If 
total bilirubin is elevated, then fractionated direct bilirubin can be measured. Amylase, lipase, coagulation factors, 
and uric acid are measured at the discretion of the investigators. Check D-dimer and ferritin levels when clinically 
indicated.  
g Missing lab tests of LDH, magnesium and phosphorous at the time points designated may be permissible as this 
does not affect either patient safety or scientific integrity of the protocol 
h Respiratory specimens (nasopharyngeal or oropharyngeal swabs).  
I Missed  correlative samples may be permissible when patients are enrolled on Holidays or access to patients is 
limited 
j Optional visits will occur starting after Day 14/early discharge. Please refer to section 7.5
 

8 
 
Study Glossary 
 
AE 
 
 
Adverse Event 
ALP 
 
 
Alkaline Phosphatase 
ALT 
 
 
Alanine Aminotransferase 
ANC 
 
 
Absolute Neutrophil Count 
AST 
 
 
Aspartate Aminotransferase 
BCC 
 
 
Best Conventional Care 
BP 
 
 
Blood Pressure 
CBC 
 
 
Complete Blood Count 
CFR 
 
 
The Code of Federal Regulations 
CI 
 
 
Confidence Interval 
CNS 
 
 
Central Nervous System 
CRF 
 
 
Case Report Form 
CRP 
 
 
C Reactive Protein 
CRS 
 
 
Cytokine Release Syndrome 
CTCAE  
 
Common Terminology Criteria for Adverse Events 
DOR 
 
 
Duration Of Response 
DSM 
 
 
Data and Safety Monitoring 
ECG 
 
 
Electrocardiogram 
eCRF 
 
 
Electronic Case Report Form 
FDA 
 
 
Food and Drug Administration 
FDAAA  
 
Food and Drug Administration Amendments Act 
FDAMA  
 
Food and Drug Administration Modernization Act 
GCP 
 
 
Guideline for Good Clinical Practice 
h, hr 
 
 
Hour 
Hgb 
 
 
Hemoglobin 
HR 
 
 
Heart Rate 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Conference on Harmonization 
ICJME  
 
International Committee of Medical Journal Editors 
IND 
 
 
Investigational New Drug 
IPIM 
 
 
Investigational Product Instructional Manual 
IRB 
 
 
Institutional Review Board 
IV 
 
 
Intravenous 
LDH 
 
 
Lactate Dehydrogenase 
MHC 
 
 
Major Histocompatibility Complex 
mL 
 
 
microliter 
mg 
 
 
Milligrams 
MOI 
 
 
Multiplicity Of Infection 
N, n 
 
 
Number 
OS 
 
 
Overall Survival 
PBMC  
 
Peripheral Blood Mononuclear Cells 
PK 
 
 
Pharmacokinetic 
PCR 
 
 
Polymerase Chain Reaction 
QAC 
 
 
Quality Assurance Committee 
RT-PCR 
 
Reverse-Transcriptase Polymerase Chain Reaction 
RBC 
 
 
Red Blood Cell 
SAE 
 
 
Serious Adverse Event 
SD 
 
 
Standard Deviation 
SEM 
 
 
Standard Error of Mean 
SFU 
 
 
Safety Follow-UP 
SOC 
 
 
Standard Of Care 
TBL 
 
 
Total Bilirubin 
VPN 
 
 
Virtual Protected Network 
WBC 
 
 
White Blood Cell 
WHO 
 
 
World Health Organization 
 

9 
 
Table of Contents 
Key Personnel ......................................................................................................................... 2 
Protocol Synopsis .................................................................................................................... 3 
Schedule of Activities ............................................................................................................... 7 
Study Glossary ........................................................................................................................ 8 
1. 
BACKGROUND, CONCEPT AND RATIONAL ............................................................. 11 
1.1. 
COVID-19 ........................................................................................................ 11 
1.2. 
Imatinib and lysosomal Sequestration .................................................................. 11 
1.3. 
Anti-Viral Activity of Imatinib ............................................................................ 12 
1.4. 
Anti-Inflammatory Activity of Imatinib ................................................................ 13 
1.5. 
Rationale: Imatinib for Treatment of COVID-19 ................................................... 16 
1.6. 
Best Conventional Care ...................................................................................... 19 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................. 19 
2.1. 
Primary Objectives ............................................................................................ 19 
2.2. 
Primary Endpoint .............................................................................................. 19 
2.3. 
Secondary Endpoints .......................................................................................... 19 
2.4. 
Exploratory Endpoints ........................................................................................ 20 
3. 
CRITERIA FOR STUDY PARTICIPANT ELIGIBILITY ................................................. 20 
3.1. 
Inclusion Criteria ............................................................................................... 20 
3.2. 
Exclusion Criteria .............................................................................................. 20 
3.3. 
Inclusion of Women and Minorities ..................................................................... 21 
4. 
RECRUITMENT PLAN AND REGISTRATION PROCEDURES ..................................... 21 
5. 
EXPERIMENTAL PLAN .............................................................................................. 22 
5.1. 
Study Design..................................................................................................... 22 
5.2. 
Study Drugs ...................................................................................................... 22 
5.3. 
Replacement of Participant ................................................................................. 24 
5.4. 
Estimated Study Duration and End of Study .......................................................... 24 
6. 
DOSE MODIFICATION AND STUDY DISCONTINUATION ......................................... 24 
6.1. 
Dose Modification and Interruption ..................................................................... 24 
6.2. 
Study Discontinuation ........................................................................................ 24 
7. 
STUDY ASSESSMENTS/PROCEDURES ...................................................................... 25 
7.1. 
Informed Consent and Demographics ................................................................... 25 
7.2. 
Medical History ................................................................................................. 25 
7.3. 
General Physical Examination ............................................................................. 25 
7.4. 
Laboratory Assessments ..................................................................................... 26 
7.5. 
Optional Visits .................................................................................................. 26 
7.6. 
Schedule of Assessments (Study Calendar) ........................................................... 26 

10 
 
8. 
REPORTING ADVERSE EVENTS / REGULATORY REQUIREMENTS ......................... 27 
8.1. 
Definitions ........................................................................................................ 27 
8.2. 
Reporting of Adverse Events ............................................................................... 27 
8.3. 
Reporting of Serious Adverse Events ................................................................... 28 
8.4. 
Data Safety Monitoring Plan ............................................................................... 29 
8.5. 
Compliance with Laws and Guidance ................................................................... 29 
8.6. 
Institutional Review Board (IRB) ........................................................................ 29 
8.7. 
Clinical Trial Monitoring .................................................................................... 29 
8.8. 
FDA Reporting .................................................................................................. 30 
8.9. 
Records Retention ............................................................................................. 30 
8.10. 
Compliance with Trial Registration and Results Posting Requirements .................... 30 
8.11. 
Data Management .............................................................................................. 30 
9. 
ADMINISTRATIVE AND LEGAL OBLIGATION ......................................................... 30 
9.1. 
Protocol Amendments and Study Termination ....................................................... 30 
9.2. 
Investigator Responsibilities for Data Collection ................................................... 31 
9.3. 
Language .......................................................................................................... 31 
9.4. 
Publication Policy .............................................................................................. 31 
9.5. 
Compensation ................................................................................................... 31 
10. 
STATISTICAL CONSIDERATIONS ............................................................................. 31 
10.1. 
Randomization .................................................................................................. 31 
10.2. 
Primary endpoint ............................................................................................... 32 
10.3. 
Sample size estimation and power ....................................................................... 32 
10.4. 
Secondary endpoints .......................................................................................... 32 
10.5. 
Interim analysis ................................................................................................. 32 
10.6. 
Safety profile .................................................................................................... 32 
10.7. 
Analysis of Efficacy Endpoints ........................................................................... 32 
11. 
CORRELATIVE SCIENTIFIC STUDIES ....................................................................... 33 
11.1. 
Viral Shedding .................................................................................................. 33 
11.2. 
Peripheral blood collection ................................................................................. 33 
11.3. 
Serology ........................................................................................................... 33 
12. 
REFERENCES ............................................................................................................. 33 
 
 
 
 

11 
 
1. BACKGROUND, CONCEPT AND RATIONAL 
 
1.1. 
COVID-19 
A novel coronavirus, called SARS-CoV-2, has caused a pandemic of respiratory illness 
termed COVID-19.1,2 By April 24th 2020, approximately 2,800,000 confirmed cases are reported 
from 187 countries, areas or territories with approximately 194,000 confirmed deaths.3 In the US, 
there are ~900,000 confirmed cases with ~50,000 deaths.3 The clinical manifestation of COVID-
19 ranges from self-limiting and mild respiratory tract illness in approximately 80% of cases to 
progressive pneumonia, multi-organ failure, and death.4,5 Although several groups around the 
globe are actively working on development of treatment(s) for COVID-19; to date, no specific 
small molecule, biologics including monoclonal antibodies, or vaccine has been approved for this 
viral disease.   
 
1.2. 
Imatinib and lysosomal Sequestration 
Imatinib mesylate is a small molecule kinase inhibitor approved by the FDA for the 
treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia 
(CML), Ph+ acute lymphoblastic leukemia (Ph+ ALL), myelodysplastic/myeloproliferative 
diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor), systemic 
mastocytosis (SM) without the D816V c-Kit mutation, hypereosinophilic syndrome (HES) and/or 
chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase, unresectable, 
recurrent and/or metastatic dermatofibrosarcoma protuberans, Kit (CD117) positive unresectable 
and/or metastatic as well as adjuvant treatment of malignant gastrointestinal stromal tumors 
(GIST). 
Imatinib film-coated tablets contain imatinib mesylate equivalent to 100 mg or 400 mg of 
imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl-1-
piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide 
methanesulfonate and its structural formula is: 
 
Imatinib mesylate is soluble in aqueous buffers ≤ pH 5.5 but is slightly soluble to 
insoluble in neutral/alkaline aqueous buffers. Lysosomal sequestration and accumulation of weak 
base tyrosine kinase inhibitors (TKIs) including imatinib has been reported by several groups.6-9  
 

12 
 
 
Figure 1. Weak-base drug distribution with lysosomal sequestration, uncharged molecules can freely diffuse across 
the lysosomal and plasma membranes while protonated (charged) molecules are trapped inside the acidic 
environment of lysosomes10 
 
In a study using fluorescent microscopy to establish subcellular localization of imatinib, 
the investigators reported high intracellular uptake and retention (IUR) of imatinib in different cell 
lines.11 The IUR of imatinib was time-, dose-, temperature-, and energy-dependent suggesting that 
plasma membrane imatinib transporters do not substantially contribute to the IUR of imatinib. 
Importantly, co-exposure with weak bases such as prazosin, amantadine, and NH4Cl significantly 
altered the IUR of imatinib, likely due to lysosomal retention and accumulation of imatinib. Co-
staining experiments with LysoTracker Red confirmed lysosomal sequestration of imatinib. The 
authors concluded that intracellular imatinib levels are primarily determined by lysosomal 
sequestration of imatinib and do not depend on the expression of imatinib transporters on plasma 
membrane.11 
In another study, the investigator reported the direct label-free visualization and 
quantification of imatinib inside living cells using hyperspectral stimulated Raman scattering 
imaging.12 Compared to the extracellular drug, imatinib was enriched over 1000-fold in the 
lysosome within several hours as a result of its lysosomotropic property. Co-administration of 
imatinib with high dose chloroquine alkalinized intralysosomal vesicle, slightly (~5-fold) 
decreased intralysosomal concentration of imatinib but did not change the intralysosomal 
concentration of chloroquine.12 This study confirmed the accumulation and intracellular drug-drug 
interaction of weak bases such as imatinib and chloroquine with label-free imaging. 
 
1.3. 
Anti-Viral Activity of Imatinib  
 
Imatinib mesylate is a known inhibitor of the Abelson murine leukemia viral oncogene 
homolog 1 (ABL1) pathway. The ABL1 pathway is a signaling pathway involved in cell 
differentiation, cell adhesion, and the cellular stress response. Overactivation of the ABL1 
pathway can lead to CML. Imatinib mesylate inhibit SARS-CoV and MERS-CoV with 
micromolar EC50s (range, 9.8 to 17.6 µM) and low toxicity (Figure 2).13 SARS-CoV does appear 
to be more sensitive to the ABL1 inhibitor than MERS-CoV. 
Imatinib mesylate has been reported to block egress of Ebola virus and of poxviruses and 
entry of coxsackievirus.14-16 These data suggest that the ABL1 pathway may be important for 
replication of many different virus families and, therefore, inhibitors of this pathway have the 
potential to be broad-spectrum antivirals.13 Mechanism of action studies showed that ABL1 

13 
 
tyrosine kinase controls budding or release of poxviruses and Ebola virus, demonstrating that the 
c-ABL1 kinase signaling pathways may play a role in the egress of these viruses. Frieman and his 
colleagues reported that “kinase signaling may also be important for replication of two members 
of the Coronaviridae family, SARS-CoV and MERS-CoV. Imatinib mesylate.”13 The step in viral 
replication in which these kinases are involved will need to be investigated further. In vivo studies 
performed in the mouse model of vaccinia virus infection demonstrated that imatinib mesylate 
was effective in blocking dissemination of the virus.16  
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Antiviral activity of imatinib mesylate. Vero E6 cells were infected with MERS-CoV or SARS-CoV at an 
MOI of 0.1 or 1, respectively, and treated for 48 h with eight doses of imatinib mesylate (B). Antiviral activity is 
shown in blue, and cytotoxicity is shown in red. EC50s are indicated. Results are representative of one experiment 
(means SEM; n = 2).13  
 
1.4. 
Anti-Inflammatory Activity of Imatinib  
 
Anti-inflammatory activity of imatinib has been reported in preclinical and clinical 
settings. Amelioration of bleomycin-induced17 and radiation-induced18 pulmonary inflammation 
and fibrosis in mouse models were reported by imatinib as monotherapy or in combination with 
other agents. Wolf and colleagues provided strong evidence that imatinib has potent anti-
inflammatory effects by reporting that it potently inhibited LPS- and Con A-induced TNFα 
production by human myeloid cells in vitro (peripheral blood mononuclear cells, CD14-selected 
monocytes, and monocyte-derived macrophages).19 Using several murine models of acute 
hepatitis, the investigator verified the in vitro findings, as imatinib prevented macrophage- and 
TNFα-dependent inflammatory damage of the liver induced by injection of either galactosamine 
or LPS by inhibition of hepatic TNFα production.19  
Interestingly, and perhaps the most relevant to COVID-19-induced acute lung injury/acute 
respiratory distress syndrome (ALI/ARDS) is the study performed by Rizzo and colleagues.20 The 
investigators assessed the effectiveness of imatinib in a “two-hit” model of ALI caused by 
combined LPS and ventilator-induced lung injury (VILI), See Figures 2 and 3. 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, See Figure 4.20 In another experiment, imatinib attenuated ALI when given 4 hours after 
LPS, suggesting potential efficacy when given after the onset of injury.20 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 ARDS on mechanical ventilation. 

14 
 
 
Figure 3. Imatinib attenuates vascular leak in mice challenged with a 2-hit model of LPS and mechanical ventilation 
(MV). Mice were challenged with LPS [0.5 mg/kg, intratracheally (it)] (t = 0 h) and MV (respiratory rate 75, tidal 
volume 30 ml/kg, positive end-expiratory pressure 0 cm H2O) (t = 20–24 h) as outlined in A. Spontaneously breathing 
(SB) control mice received PBS (vs. LPS) and were intubated for 4 h without MV. Bronchoalveolar lavage (BAL) 
fluid, plasma, and lungs were harvested from the animals immediately after MV. Imatinib (IM) (75 mg/kg, ip) or 
vehicle was administered 0.5 h before LPS administration and before the initiation of MV. Lung permeability was 
assessed by BAL protein content (B), BAL fluid albumin (C), and lung tissue albumin (D). Additionally, in separate 
animals, Evans Blue dye (EBD) was injected (30 mg/kg, iv) 1 h before harvest, and representative extravasation into 
harvested lung tissue is shown (E) and quantified in multiple samples (F). The left lung of each of these animals was 
used for calculation of lung wet:dry ratio (G). SB (n = 3), SB + imatinib (n = 3), LPS + ventilator-induced lung injury 
(VILI) (n = 3–11) and LPS + VILI + imatinib (n = 3–6). *P < 0.05 compared with SB controls and #P < 0.05 
compared with untreated animals.20 

15 
 
 
 
Figure 4. Imatinib decreases lung inflammation in mice challenged with LPS and MV. Mice were subjected to the 2-
hit lung injury model (LPS + VILI), and lung inflammation was quantified by BAL total cell counts (A) and BAL 
neutrophil counts (B). Representative hematoxylin and eosin (H and E)-stained lung sections are shown (C). Each H 
and E image was obtained from a different animal. SB (n = 3), SB + imatinib (n = 3), LPS + VILI (n = 3–11), and 
LPS + VILI + imatinib (n = 3–6). *P < 0.05 compared with SB controls and #P < 0.05 compared with untreated 
animals.20 
 

16 
 
 
Figure 5. Imatinib decreases LPS-induced vascular leak when given after injury onset. Mice were challenged with 
LPS (1.0 mg/kg, it) (vs. PBS) and then received imatinib (75 mg/kg, ip) (vs. vehicle) 4 h later. Samples were 
harvested 18 h after LPS administration. Pulmonary vascular permeability was quantified in these animals by 
measuring BAL protein (A), BAL albumin (B), and lung tissue albumin (C). In separate animals, EBD was injected 
(30 mg/kg, iv) 1 h before harvest, and representative extravasation into harvested lung tissue is shown (D) and 
quantified in multiple samples (E). The left lung of each of these animals was used for calculation of lung wet:dry 
ratio (F). SB (n = 3), SB + imatinib (n = 3), LPS (n = 3–6), and LPS + imatinib (n = 3–6). *P < 0.05 compared with 
SB controls and #P < 0.05 compared with untreated animals.20 
 
 
1.5. 
Rationale: Imatinib for Treatment of COVID-19 
Tolerable and efficacious treatment for patients with COVID-19 are a rapidly evolving 
therapeutic challenge and the need to develop novel and optimal regimens to treat infection or 
prevent progression to critical illness remains probably the most important medical challenge in 
early 2020 worldwide. There are numerous clinical trials currently ongoing across the globe 

17 
 
using/repurposing anti-virals, anti-malaria agents, cytokines, monoclonal antibodies and vaccines. 
In this protocol, and based on preclinical evidence, we aim to clinically examine the addition of 
imatinib to BCC for treatment of hospitalized patients with COVID-19 positivity. 
Imatinib is a weak base that accumulate in lysosomes resulting in potential broad-
spectrum antiviral activities by lysosomal alkalization required for virus/cell fusion of SARS-
CoV.21 It is demonstrated that imatinib can be trapped intralysosomally and increase endosomal 
pH12 necessary for SARS-CoV-2 cell/membrane fusion and replication. Moreover, imatinib has 
anti-inflammatory effect in acute lung injury. Because of the critical role of mechanical 
ventilation in the care of patients with ARDS, this can have a significant clinical impact for 
patients with severe COVID-19 infection in ICU.20 Mechanistic studies in mouse lung tissue and 
human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and 
activation, Figures 5 and 6.20 
 
Figure 6. Imatinib inhibits LPS-induced NF-κB phosphorylation and nuclear translocation in vitro. Human 
pulmonary artery endothelial cells (HPAEC) were treated with imatinib (40 μM, 60 min) and then challenged with 
LPS (1 μg/ml, 0–60 min). Lysates were harvested for Western blots for phosphorylated NF-κB p65 (S536), total NF-
κB p65 protein, IκB, and actin and quantified by densitometry (A and B). HPAEC plated on glass coverslips were 
subjected to identical conditions, and immunofluorescence microscopy was conducted to determine the localization 
of total NF-κB p65 protein (red). 4′,6-diamidino-2-phenylindole (DAPI) (blue) was used to stain the nuclei (white 
arrows) (C). Data are representative of 3 independent experiments. *P < 0.05 compared with nonchallenged 
samples.20 
 

18 
 
 
Figure 7. Imatinib decreases NF-κB expression in mouse lungs after LPS. Mice were challenged with LPS (1.0 
mg/kg, it) (vs. PBS) and then received imatinib (75 mg/kg, ip) (vs. vehicle) 4 h later. Lung tissue homogenates were 
collected, subjected to Western blotting for total NF-κB p65 protein, and quantified by densitometry (A and B). Lanes 
in A represent lung homogenates from individual animals. Representative immunohistochemistry images are shown 
for NF-κB p65 taken by an individual blinded to experimental condition (C). *P < 0.05.20 
 
It is important to address the clinical safety and availability of imatinib. Imatinib is 
clinically available worldwide and have been in clinical practice for several years with very well-
known adverse event profiles. It is tolerable as single-agent for patients with hematological 
disorders.22,23 Considering the half-life and other pharmacologic properties of imatinib, it is 
expected that the intended effect of the drug should be manifested by 14 days in this patient 
population. 
 
 

19 
 
1.6. 
Best Conventional Care 
All participants will receive the best conventional care (BCC) available according to local 
practice standards. Taking into account that practice standards will evolve as data from multiple 
ongoing studies become available, BCC may change overtime. In this study the BCC may 
include, but is not limited to: use of antipyretics, anti-infectives including antivirals, anti-
inflammatory agents, immunomodulators, supplemental oxygen, non-invasive and invasive 
ventilation, vasopressor support, renal-replacement therapy, and ECMO.  
Therapies that are shown to be effective but may not be licensed will 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. OBJECTIVES AND ENDPOINTS 
 
2.1. 
Primary Objectives 
To evaluate the efficacy and safety of oral administration of imatinib combined with BCC vs. 
placebo plus BCC in hospitalized patients with COVID-19 
2.2. 
Primary Endpoint 
The primary endpoint is all-cause mortality at Day 28 after the start of imatinib/placebo.  
2.3. 
Secondary Endpoints 
 All-cause mortality at Day 60 after the start of imatinib/placebo 
 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. This endpoint of clinical improvement has 
been used before in clinical trials in patients hospitalized with severe influenza24 and 
with COVID-1925 infection, and it was recommended by the WHO R&D Blueprint 
expert group26. 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. 
 Time to a 2-point clinical improvement difference over baseline 
 Duration of hospitalization 
 Duration of ECMO or invasive mechanical ventilation (for participants on ECMO of 
mechanical ventilation at Day 1) 
 Duration of ICU stay/requirement (for participants in ICU at Day 1) 
 Proportion of participants with treatment-related serious adverse events 
 Proportion of participants who discontinue study treatment due to adverse events 
Proportion of patients with a negative oropharyngeal or nasopharyngeal swab for 
SARS-CoV-2 by quantitative RT PCR on days 14 and 28 

20 
 
2.4. 
Exploratory Endpoints 
 Obtain blood/PBMCs for storage to look at transcriptomics in severe disease 
 Association of MHC with severity of illness  
 Mean change in the ordinal scale from baseline 
 Time to an improvement of one category from admission using an ordinal scale 
 Duration of hospitalization 
 Duration of new oxygen use 
 Number of oxygenation free days 
 Duration of new mechanical ventilation 
 Number of ventilator free days 
3. CRITERIA FOR STUDY PARTICIPANT ELIGIBILITY 
 
3.1. 
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 outside or local laboratory within 7 days 
of randomization. 
4. Women of childbearing potential must agree to use at least one primary form of 
contraception for the duration of the study. 
3.2. 
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, remdesivir, or immunomodulators is not an 
exclusion criterion. 
2. Pregnant or breastfeeding women 
3. Patients with significant liver dysfunction at screen as defined as: 
a. Total bilirubin > 2.5 mg/dL 
b. ALT > 5 x upper limit of normal 
4. Patients with significant hematologic disorder at screen as defined as:  
a. Absolute neutrophil count (ANC) < 200/µL 
b. Platelet < 20,000/µL 
c. 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 
participant unsuitable for the study.  

21 
 
3.3. 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. RECRUITMENT PLAN AND REGISTRATION PROCEDURES 
 
Informed consent is a process that is initiated prior to the individual agreeing to participate 
in the study and continues throughout the individual’s study participation. The informed consent 
form is IRB-approved and the participant will be asked to read and review the document.   
Due to the excessive risk of COVID-19 transmission and to preserve limited personal protective 
equipment (PPE) for essential procedures, a remote consenting process will be used. The 
following considerations for remote informed consenting should be followed: 
 The investigator and/or his designee is responsible for presenting the risks and benefits of 
study participation to the patient in simple terms using the informed consent document.  
 Potential participants will be given an informed consent form (either paper or electronic 
document in a portable electronic device) and allowed time to read this document.  
 The elements of the informed consent, including discussion of the risk and benefits, will 
be done either over the phone or via remote video conferencing methods approved by the 
IRB. 
 Research team member will document how the consent form was transmitted or given to 
participant, and what method was used to communicate the informed consent.   
 The investigator will ensure that written informed consent is obtained from each 
participant or legally authorized representative by obtaining the appropriate signatures and 
dates on the informed consent document before the performance of protocol evaluations or 
procedures.  
 Signatures may be obtained using the following options: (1) electronic signature, or (2) 
photograph of signature/signature page sent back to study team.  
 Participants must date the informed consent form to be valid. 
 Study team member should document how signature was obtained. 
 
If unable to obtain a participant signature on an informed consent document, the following 
should be followed: 
 Document the method used for communication with the participant 
 Document means by which agreement was communicated; 
 Document that no imaging technology was available to capture a signed consent form; 
 A witness to the process and a witness sign and date the informed consent form. 
 
Participants must be informed that participation is voluntary and that they may withdraw 
from the study at any time, without prejudice. Copies of the informed consent documents will be 
given to the participants for their records. The informed consent process will be conducted and 
documented in the source document (including the date) before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
For participants who are too unwell to provide consent such as participants on invasive 
ventilator or ECMO, Legally Authorized Representative (LAR) can sign the informed consent. 
At the time of consent, a unique participant ID number will be assigned to the participant 
by UMMC. If for some reason the participant rescreens, the same participant ID number will be 
assigned to the participant for rescreening. 

22 
 
Once the signed informed consent has been obtained and all pretreatment evaluations have 
been performed, eligibility of the participant will be reviewed by the Lead Protocol Coordinator 
and the PI. Only eligible participants will be enrolled on the study.  
The following documents will be compiled by the Lead Protocol Coordinator, PI, or other 
study team member for eligibility verification:  
o Signed informed consent form (ICF) 
o Copy of required laboratory tests including chemistry, CBC, bilirubin, LFT, RT-PCR 
assay results, and evidence of negative pregnancy test results for eligible participants  
o Completed Eligibility worksheet 
If the participant is deemed eligible for enrollment, the Lead Protocol Coordinator, PI, or 
other study team member will forward the completed packet to the Lead Data Manager (DM). 
The PI or sub-Is determine stratification and approves the start of treatment. The approval will be 
communicated to investigational drug service (IDS) pharmacy by the Lead Protocol Coordinator, 
PI, or other study team member, and IDS pharmacy will then randomize the patient. The 
participant will then be registered in OnCore and assigned a primary DM by the Lead DM.  
Following enrollment, participants should begin protocol treatment within 3 days. Issues 
that would cause treatment delays should be discussed with the PI (Dr. Levine). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the study 
may be canceled.  
 
5. EXPERIMENTAL PLAN 
 
5.1. 
Study Design 
This is an individual patient-level, randomized, double-blind, placebo-controlled phase 3 
clinical trial at the University of Maryland Medical System, MD.  Eligible patients are randomly 
assigned in 2 [imatinib] : 1 [placebo] ratio to receive either tyrosine kinase inhibitor imatinib or 
placebo for 14 days. In both arms, all study participants receive the best available conventional 
supportive care according to local practice standards. Taken into account that there are many 
national and international studies are ongoing, the BCC may change overtime. In this study the 
BCC may include, but not limited to, antipyretics, anti-infectives including antivirals (e.g. 
remdesivir), anti-inflammatory agents (e.g. chloroquine analogues, monoclonal antibodies, IL-6 
receptor inhibitors, etc.), supplemental oxygen, non-invasive and invasive ventilation, vasopressor 
support, renal-replacement therapy, and ECMO. In both arms, participants can receive 
concomitant antibiotics at the discretion of the treating physician as necessary. 
In order to balance the severity of the respiratory illness between the two arms, per FDA 
recommendation randomization are stratified based on radiographic findings and oxygen 
requirements: 1) Severe disease: evidence of pneumonia on chest X-ray or CT scan or chest 
auscultation (rales, crackles), and SpO2 ≤ 92% on ambient air or PaO2/FiO2 < 300 mmHg, and 
requires supplemental O2 administration by nasal cannula, simple face mask, or other similar 
oxygen delivery device; 2) Critical disease: requires supplemental O2 delivered by non-rebreather 
mask or high flow cannula or use of invasive or non-invasive ventilation or requiring treatment in 
an icu, use of vasopressors, extracorporeal life support, or renal replacement therapy.  
The trial is conducted in accordance with the principles of the Declaration of Helsinki and 
the Good Clinical Practice guidelines of the International Conference on Harmonization. 
 
5.2. 
Study Drugs 
 
Imatinib 

23 
 
All doses of imatinib should be administered with a meal and a large glass of water. 
Imatinib can be dissolved in water or apple juice for participants having difficulty swallowing. In 
this study, participants with confirmed COVID-19 positive tests receive imatinib for total of 14 
days; 400 mg orally daily Days 1-14. Imatinib 400 mg tablets will be encapsulated using size 000 
capsules and cellulose microcrystalline filler. For participants on ventilator or ECMO, imatinib 
will be given as oral suspension (40 mg/mL). To make the oral suspension, imatinib tablets will 
be crushed and mixed in Ora-sweet solution to yield a concentration of 40 mg/mL suspension by 
pharmacy. Additionally, in the absence of supportive microbiological testing results, we confirm 
that the in-use stability period for the prepared imatinib suspensions will be 24 h at room 
temperature or 7 days at refrigerated conditions. 
Due to the COVID-19 crisis, healthcare professionals (nursing staff in particular) are faced 
with the major burden of caring for critically patients, such as those on ventilators or ECMO. We 
believe that it to be impractical to request nursing staff to prepare imatinib oral solution by 
immersing on the floor. Additionally, we also believe this practice could result in dosing errors if 
tablets are not fully dissolved and may compromise the medication during preparation. The local 
pharmacy staff will prepare imatinib oral suspension under hazardous hood with proper protected 
equipment, which is vented to outside and meet USP Pharmaceutical Compounding guidelines. 
Lastly, pharmacy staff will be educated regarding risk associated with crushing and handling of 
imatinib and required protective measures. The pharmacy staff will follow the American Society 
Health-System Pharmacists (ASHP) guidelines for handling hazardous drugs. 
The pharmacokinetics (PK) of imatinib have been evaluated in studies in healthy 
participants and in population PK studies in over 900 participants. Imatinib is well absorbed after 
oral administration with Cmax achieved within 2-4 h post-dose. Mean absolute bioavailability of 
imatinib is 98%. There is no significant change in the PK of imatinib on repeated dosing, and 
accumulation is 1.5- to 2.5-fold at steady state when imatinib is dosed once-daily. At clinically 
relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is 
approximately 95%, mostly to albumin and α1-acid glycoprotein.23 
For Warnings, Precautions, Drug interactions, and Geriatric use, see attached FDA Label 
for Imatinib dated 08/21/2018. 
 
Placebo 
The matching placebo will be packaged by the IDS Pharmacy of the site. The placebos 
will be prepared using size 000 capsules and cellulose microcrystalline filler. Imatinib 400 mg 
capsules and placebo capsules will be identical form and color. For participants on ventilator or 
ECMO, placebo will be given as oral suspension with similar process for making imatinib 
suspension. 
 
Concomitant Medications/Supportive Care 
In both arms, participants can receive concomitant available local standard of care 
antipyretics, antibacterials, antivirals, antifungals and anti-inflammatory agents at the discretion of 
the treating physician as necessary. For other drug-drug interaction particularly with CYP P450, 
the treating physician should consider risk and benefit of drug administration based on available 
information. 
Co-administration of off-label immunomodulatory treatments for COVID-19 including but 
not limited to corticosteroids, sarilumab, clazakizumab, tocilizumab, and anakinra will be allowed 
but may affect interpretability of study outcomes. The timing, dosing, and duration of these 
treatments will be meticulously collected, including any of these treatments that may be used for 
participants who experience progression of COVID-19 disease after study enrollment. Two 
analyses will be performed, the primary analysis will compare the primary endpoint in the two 

24 
 
trial arms irrespective of any other treatment; the second analysis will be stratified for co-
administration of immunomodulatory drugs. 
Concomitant medications used in the management of targeted SAEs and/or targeted AEs 
will be collected and recorded in the electronic case report forms. 
 
5.3. 
Replacement of Participant 
 
The primary analysis will be conducted using a strict intention to treat principle (ITT). All 
participants will be evaluable irrespective of the clinical course of their disease and the dose of 
study medication received. 
 
5.4. 
Estimated Study Duration and End of Study 
 
For an individual participant the length of participation is approximately 60 days. Per 
recommendation by the FDA, we extend the duration of follow-up to Day 60 to assess adverse 
events and mortality. FDA recommended that telephone visits (or telemedicine) could be 
considered if clinic visits are not feasible. 
End of Trial is defined as the time when the last participant is assessed or receives an 
intervention for the purposes of final data collection for the primary endpoint of the study. End of 
study for individual participant is defined as the last day that protocol-specified assessments are 
conducted for an individual participant.  
 
6. DOSE MODIFICATION AND STUDY DISCONTINUATION 
 
6.1. 
Dose Modification and Interruption 
 
Participants can remain on the study if they at least receive 80% of pre-specified dosages 
of placebo or imatinib, i.e. participants may miss < 20% of the scheduled drug dosages for 
medical reason(s) (at the discretion of treating physician) or administrative reason(s) such as 
temporary unavailability of a drug for a specific dose/schedule or nursing/clerical errors. 
Participants remain in the ITT analysis irrespective of dosage received. 
 
6.2. 
Study Discontinuation 
 
Treatment should be discontinued in the event of any of the following: 
 Occurrence of Grade 4 AE at least probably related to imatinib/placebo.  
 Occurrence of an AE which makes discontinuation from treatment necessary due 
to protocol-specified safety criteria or desirable in the investigator’s and/or the 
participant´s opinion  
 Investigator’s decision that a change of therapy is in the participant´s best interest 
 Intercurrent medical condition, which in the opinion of the investigator or the 
participant precludes further treatment of the participant 
 Withdrawal of participant’s consent to further study treatment 
 Death 
 Lost to follow-up 
All reasons for treatment discontinuation will be documented in the CRFs. If a participant 
fails to keep the appointments for study visits, the investigator will document the reason and 
circumstances as completely and accurately as possible. 
Participants have the right to withdraw from the study at any time and for any reason 
without prejudice to his or her future medical care by the physician or at the institution.
Participants can decline to continue receiving protocol-specified therapies or procedures at 
any time during the study but continue participation in the study. If this occurs, the Investigator is 
to discuss with the participant the appropriate processes for discontinuation from protocol-

25 
 
specified therapies and must discuss with the participant the options for continuation of the 
Schedule of Assessments and collection of data, including endpoints and AEs. The Investigator 
documents the change to the Schedule of Assessments and the level of follow-up that is agreed to 
by the participant (e.g., in person, through family/friends, in correspondence/communication with 
other physicians, from review of the medical records). 
Withdrawal of consent for a study means that the participant does not wish to receive 
further protocol-specified therapies or procedures, and the participant does not wish to or is 
unable to continue further study participation. Participant data up to withdrawal of consent will be 
included in the analysis of the study, and where permitted, publically available data can be 
included after withdrawal of consent. Per recommendation by FDA, multiple attempts will be 
made to obtain final outcomes on all participants enrolled. The primary endpoint can be assessed 
without any diagnostic tests or imaging and we expect essentially all participants to be evaluable 
with respect to this endpoint. The only exception is in case a participant wants to withdraw from 
the study and demands that his/her data not be used. We expect this to be an exceptional situation. 
 
7. STUDY ASSESSMENTS/PROCEDURES 
 
7.1. 
Informed Consent and Demographics  
All participants must sign and date the most current IRB approved ICF. All enrolled 
participants should be re-consented with any updated versions of IRB approved ICF as applicable 
and per institutional guidelines. 
Demographic data that will be collected include sex, date of birth, race, and ethnicity. 
The following assessments/procedures are to be completed during the screening period: 
Confirmation that the ICF has been signed, Eligibility confirmed based on inclusion/exclusion 
criteria, Medical history, Demographic data collection, Pregnancy test, Local laboratory 
assessments including CBC with differential and Chemistry and CRP and ECG, Participant 
Registration. Subsequent ECGs will be obtained if clinically indicated at the discretion of the 
treating physician. FDA recommends clinically indicated ECGs given the risk of QT prolongation 
and overlapping cardiac risk profiles with some or the concomitant medications. Some of the 
screening assessments/procedures completed prior to consent can be used for study purposes since 
frequent access to COVID-19 patients is restricted for nursing safety. That assessments required 
at Screening if done within 7 days of consent will be accepted and there is no need to repeat these 
assessments.  
 
7.2. 
Medical History  
The Investigator or designee will collect relevant medical history before the start of study 
and with every AE reporting. All findings are recorded on the medical history CRF. Per FDA 
recommendation, the number of days between onset of symptoms and initiation of treatment will 
be collected. 
 
7.3. 
General Physical Examination  
If weight is not able to be obtained at the time of enrollment, self-reported weight is 
acceptable. The baseline physical examination will include as much physical examination as 
clinical condition of the participants allows. The physical examination at subsequent study visits 
will consist of an interim examination to monitor for any changes from the baseline physical 
examination. Physical examination does not have to be comprehensive and is determined by the 
treating physician. For vital signs, the following measurements must be performed as outlined in 
the Schedule of Assessments: systolic/diastolic blood pressure, pulse rate, respirations and O2 
saturation, and temperature in intervals.   
 

26 
 
7.4. 
Laboratory Assessments  
Analyses for all laboratory tests used throughout this study are listed in the Study 
Calendar. All screening and on-study laboratory samples will be collected and processed at the 
investigators local laboratory and analyzed locally. If for clinical reason(s) or isolation status 
laboratory sampling cannot be performed, it does not considered protocol deviation.  
Urine or serum pregnancy tests will be performed locally on all females except for female 
participants who are surgically sterile or > 2 years postmenopausal. If the pregnancy test is 
positive at screening the participant should not be enrolled. If a standard of care pregnancy test is 
collected during the study, and the result is positive, the treating physician should contact the 
principle investigator for instructions. If a female participant, or the partner of a male participant, 
becomes pregnant during the conduct of the study it must be reported on the UMB IRB Pregnancy 
Notification Worksheet. 
7.5. 
Optional Visits 
Day 21, Day 28, or Day 60 are optional in the event that participant is discharged 
prior to these visits. Depending when the participant is discharged, the Lead Protocol 
Coordinator will conduct a telephone call on Day 28 or Day 60 as a follow-up. 
 
7.6. 
Schedule of Assessments (Study Calendar) 
 
 
ASSESSMENTS/ 
OBSERVATIONS 
Screen     
(D-3 to 
D1)
Day 1 
Day 2 
Day 5 
Day 8 
Day 10 
Day 14a 
Day 21j 
Day 28j 
Day 60b,j 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±7 d 
±7 d 
±7 d 
Informed consent
X 
  
  
  
  
  
  
  
  
Confirm eligibility
X 
X 
  
  
  
  
  
  
  
Randomization
  
X 
  
  
  
  
  
  
  
Study drug administration
  
X 
  
  
Demographics
X
Medical history
X 
  
  
  
  
  
  
  
  
Vital signs & Physical examd
X 
X 
  
X 
  
X 
X 
 X 
X  
X
Clinical assessmentse                     
X
X
CBC w diff count
X 
  
X 
X 
  
X 
X 
  
X 
X
Chemistriesf,g
X 
  
X 
X 
  
X 
X 
  
X 
X
CRPg 
X 
  
  
X 
  
  
X 
  
X 
X
ECG
X 
  
  
  
  
  
  
  
  
Pregnancy test
X 
  
  
  
  
  
  
  
  
Targeted AE assessment
X
Concomitant medication
X 
X 
  
X 
  
X 
X 
X  
X  
X
Primary endpoint assessment
  
  
  
  
  
  
X 
  
  
SARS-CoV-2 PCRh,i
X  
X 
  
X 
  
X 
X 
  
X 
Correlative/scientific studiesi 
  
X 
  
  
X 
  
X 
Screen (Day -3 to Day 1) - Screening and Day 1 visits can occur the same day.
a Early discharge visit - use Day 14 assessments
b Early termination visit - use Day 60 assessments 
c For planned 14 days
 
 
 
 
 
 
 
 
d Clinically appropriate physical exams including vital signs and O2 saturation
e Clinical assessments - 7-point ordinal scale and respiratory treatment status. Daily while hospitalized.
f Chemistries  include the following: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, magnesium, phosphorous, AST, ALT, 
total bilirubin, alkaline phosphatase, albumin, total protein, and LDH. If total bilirubin is elevated, then fractionated direct bilirubin can be measured. 
Amylase, lipase, coagulation factors, and uric acid are measured at the discretion of the investigators. Check D-dimer and ferritin levels when clinically 
indicated.  
g Missing lab tests of LDH, magnesium, phosphorous, and CRP at the time points designated  may be permissible as this does not affect either patient safety 
or scientific integrity of the protocol. 
h Respiratory specimens (nasopharyngeal or oropharyngeal swabs)  
I Missed  correlative samples may be permissible when patients are enrolled on Holidays or access to patients is limited 
j Optional visits will occur starting after Day 14/early discharge. Please refer to section 7.5

27 
 
8. REPORTING ADVERSE EVENTS / REGULATORY 
REQUIREMENTS 
 
8.1. 
Definitions  
 
Adverse Event (AE): An AE is defined as any untoward medical occurrence in a clinical 
trial participant. The event does not necessarily have a causal relationship with study treatment. 
The Investigator is responsible for ensuring that any AEs observed by the Investigator or reported 
by the participant are recorded in the participant’s medical record. 
 
CTCAE term (AE description) and Grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will 
be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site. 
Attribution of the AE:  
 Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment. 
 Unlikely – The AE is doubtfully related to the study treatment. 
 Unrelated – The AE is clearly NOT related to the study treatment. 
The Definition of a Serious Adverse Event (SAE):  
SAE is defined as any of the following: 
 Any death that occurs while the participant is enrolled in the study or within 30  
 
 
days of completing the study 
 Immediately life-threatening AE 
 Requires inpatient hospitalization 
 Prolongation of an existing hospitalization 
 Congenital anomaly/birth defect 
 Medically important event 
 Disability/incapacity (persistent or significant) 
 
8.2. 
Reporting of Adverse Events  
 
The PI is responsible for monitoring the safety of participants who have entered this study 
and for alerting the UMGCCC Data and Safety Monitoring and Quality Assurance Committee 
(DSM/QAC) as well as the FDA to any event that seems unusual, even if this event maybe 
considered an unanticipated benefit to the participant. 
Only the following targeted AEs if not present at the baseline and occur at any time during 
the clinical study or within 30 days of receiving the last dose of study medication, whether or not 
related to the study drug/placebo, will be collected by the study team into the Case Report Forms. 
Targeted AEs: 
 Infections and infestations ≥ Grade 3 events 
 Deep Vein Thrombosis (DVT) and other thromboembolic event 
 Disseminated intravascular coagulation (DIC) 
 Cytopenia including anemia ≥ Grade 3, thrombocytopenia ≥ Grade 3, neutropenia 
≥ Grade 3 
 Adult Respiratory Distress Syndrome (ARDS) and respiratory acidosis 
 Significant pulmonary changes from baseline (as indicated in relevant Imaging) 

28 
 
 Significant new arrhythmia 
 Decreased LVEF 
 ALT increased ≥ Grade 3, AST increased ≥ Grade 3, Direct bilirubin increased ≥ 
Grade 3 
 Acute Kidney Injury, Significant creatinine increased ≥ Grade 3 
 Periorbital edema, lower extremity edema, pericardial effusion, pleural effusion 
After a study participant’s completion of or discontinuation from the study, the 
investigator remains responsible to follow, through an appropriate health care option, AEs that are 
serious or that caused the study participant to discontinue before completing the study. 
 
8.3. 
Reporting of Serious Adverse Events  
 
The following serious adverse experiences (SAEs) which occur at any time during the 
clinical study or within 30 days of receiving the last dose of study medication, whether or not 
related to the study drug, will be collected by the study team into the Case Report Forms.  
Targeted SAEs: 
 Infections and infestations ≥ Grade 3 events 
 Deep Vein Thrombosis (DVT) 
 Disseminated intravascular coagulation (DIC) 
 Thromboembolic event 
 Anemia ≥ Grade 3 
 Thrombocytopenia ≥ Grade 3 
 Neutropenia ≥ Grade 3 
 Adult Respiratory Distress Syndrome (ARDS) 
 Respiratory acidosis 
 Significant pulmonary changes from baseline (as indicated in relevant Imaging) 
 Significant new arrhythmia 
 Decreased LVEF 
 Alanine aminotransferase (ALT) increased ≥ Grade 3 
 Aspartate aminotransferase (AST) increased ≥ Grade 3 
 Blood bilirubin increased ≥ Grade 2 
 Acute Kidney Injury 
 Significant creatinine increased ≥ Grade 2 
 Periorbital edema 
 Lower extremity edema 
 Pericardial effusion 
 Pleural effusion 
If the event meets the criteria for FDA mandatory IND safety reporting (serious + related 
+ unexpected), the UMMC will report the event to the FDA using the MedWatch form (FDA 
Form 3500A). Events which are assessed as “unexpected fatal or life-threatening” should be 
reported to FDA as soon as possible, but no later than 7 calendar days following the initial receipt 
of the information. All other unexpected suspected SAEs suggesting significant risk to human 
participants should be reported to FDA no later than 15 calendar days following the initial receipt 
of the information. 
After a study participant’s completion of or discontinuation from the study, the 
investigator remains responsible to follow, through an appropriate health care option, AEs that are 
serious or that caused the study participant to discontinue before completing the study.  

29 
 
The procedure is as follows: All deaths should be reported immediately; If the SAE was 
unexpected and possibly, probably, or definitely related to the drug, the investigator or designee 
must initiate the reporting process within 24 h of being made aware of the event; The FDA is to 
be informed of any serious AEs in accordance with established guidelines using the standard 
MedWatch forms (FDA Form 3500A). 
 
8.4. 
Data Safety Monitoring Plan  
 
It is the responsibility of the PI to oversee the safety of the study. This safety monitoring 
will include careful assessment and appropriate reporting of AEs as noted above. This study will 
be monitored by the UMGCCC DSM/QAC and will follow the Data Safety and Monitoring Plan 
as outlined in the Clinical Investigator Handbook of the UMGCCC Clinical Research Office. The 
DSM/QAC will meet after each 25 participants are enrolled or every 6 months whichever comes 
sooner. AE profile of imatinib is well known. Due to the dynamic environment of best 
conventional care, defined halting rules may not apply to future best conventional care processes. 
Enrollment halting may occur by DSM/QAC based on interim/cumulative data for evidence of 
study-related AEs including anticipated toxicities, such as ECG parameters, SAEs and laboratory 
parameters. At the official request of the DSM/QAC, the study can be unblinded. This decision 
will be discussed by the PI and other investigators as well as with the regulatory agencies 
including UMB IRB and FDA. 
 
8.5. 
Compliance with Laws and Guidance  
 
This study is conducted in accordance with current U.S. FDA Regulations, Good Clinical 
Practices (GCPs) and International Counsel on Harmonization (ICH) E6 Guidelines. The 
investigator and their sub-investigators will sign financial disclosure forms prior to participating 
in the study and one year post end of study (21 CRF 54.1-54.6). 
 
8.6. 
Institutional Review Board (IRB)  
 
This protocol was submitted to and approved by the University of Maryland IRB. Study 
procedures began once IRB approval was secured. All amendments, instances of reportable new 
information (i.e. unanticipated problems, data breaches, etc.) and continuing review reports will 
be submitted to the University of Maryland IRB per institutional policy. 
 
8.7. 
Clinical Trial Monitoring  
 
Source Data verification monitoring will be conducted in accordance with the 
Greenebaum Comprehensive Cancer Center Sponsor-Investigator Monitoring Standard Operating 
Procedure (SOP), the Code of Federal Regulations (CFR), and FDA and ICH E6 Guidelines. This 
will include central verification of eligibility of each participant enrolled and risk based 
monitoring strategies. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for inspection at 
any time by representatives from UMGCCC and/or applicable regulatory authorities. 
Elements to include are participant files containing ICFs and participant identification list, 
study files containing the protocol with all amendments, copies of pre-study documentation, and 
all correspondence to and from the IRB,  Investigational product-related correspondence 
including Proof of Receipts (POR), Investigational Product Accountability Record(s), Return of 
Investigational Product for Destruction Form(s), Final Investigational Product Reconciliation 
Statement, as applicable. In addition, all original source documents supporting entries in the CRFs 
must be maintained and be readily available. 

30 
 
The Clinical Monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to local regulations on the conduct of clinical research. The Clinical Monitor is to 
have access to participant medical records and other study-related records needed to verify the 
entries on the CRFs. 
The Investigator agrees to cooperate with the Clinical Monitor to ensure that any problems 
detected during these monitoring visits, including delays in completing CRFs, are resolved. 
 
8.8. 
FDA Reporting  
 
The FDA Annual Report will be submitted to the Agency within +/- 60 days of the date on 
the IND approval letter. Major amendments will be submitted to FDA at the time of IRB 
submission. Minor amendments will be reported to FDA at the time of the next major amendment 
or at the next FDA Annual Report (whichever comes first). 
 
8.9. 
Records Retention 
 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. Records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, ICFs, 
laboratory test results, and medication inventory records will be maintained in secure offsite 
storage after completion of study follow-up and data analysis. 
 
8.10. 
Compliance with Trial Registration and Results Posting Requirements 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), Dr. Levine submitted the 
protocol to the Clinical Trials Data Bank, http://www.clinicaltrials.gov and received the identifier 
NCT: 04394416.  
 
8.11. 
Data Management 
 
Source documents are original documents, data, and records from which the participant’s 
CRF data are obtained. These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, radiographs, and correspondence. 
Clinical data will be entered into the OnCore® database either by remotely accessing 
OnCore® via Virtual Protected Network (VPN) or by the designated data manager at the 
UMGCCC. Oncore® is 21CRF11.10 (electronic medical records) compliant and is equipped for 
HIPAA compliant internet-based entry of protocol tracking and review information. 
All study data will be collected by the research team at each and every study visit and 
recorded in the research record. This data will then be entered in to the OnCore® study database. 
All source documents will be obtained and retained along with any study forms, and 
placed into the participant’s research folder. 
 
9.  ADMINISTRATIVE AND LEGAL OBLIGATION 
 
9.1. 
Protocol Amendments and Study Termination 
 
If the PI or other investigators wish to amend the protocol, the IRB must be informed of 
all amendments and give approval. The Investigator must send a copy of the approval letter from 
the IRB to UMGCCC. Significant changes will be reviewed by the FDA as well.  

31 
 
The Investigator is to notify the IRB in writing of the study’s completion or early 
termination. 
 
9.2. 
Investigator Responsibilities for Data Collection 
 
The Investigator is responsible to comply with the requirements for all assessments and 
data collection (including participants not receiving protocol-specified therapies) as stipulated in 
the protocol for each participant in the study. For participants who withdraw before completion of 
all protocol-required visits and are unable or unwilling to continue the Schedule of Assessments, 
the Investigator can search publically available records [where permitted] to ascertain survival 
status. This ensures that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible. 
 
9.3. 
Language 
 
CRFs must be completed in English. All written information and other material to be used 
by participants and investigative staff must use vocabulary and language that are clearly 
understood. 
 
9.4. 
Publication Policy 
 
Authorship of any publications resulting from this study will be determined based on the: 
(1) substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data; (2) drafting the article or revising it critically for important intellectual 
content; (3) final approval of the version to be published; (4) agreement to be accountable for all 
aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved. If a multicenter group has conducted the work, 
the group is to identify the individuals who accept direct responsibility for the manuscript. These 
individuals are to fully meet the criteria for authorship defined above. All persons designated as 
authors are to qualify for authorship, and all those who qualify are to be listed. Authors are 
required to meet standard ICMJE criteria. 
Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. Each author is to have participated sufficiently in the work to 
take public responsibility for appropriate portions of the content. 
 
9.5. 
Compensation 
 
Any arrangements for compensation to participants for injury or illness that arises in the 
study are described in the ICFand is available as a separate document. 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1. 
Randomization  
 
The trial is designed as a placebo-controlled, double-blind, two-parallel arm, randomized 
trial with a 1:1 allocation ratio to: 
Arm A) 
Imatinib+BCC 
Arm B) 
Placebo+BCC 
Participants in both arms can receive the supportive care per local standards at the 
discretion of the treating physician. Randomization will be completed centralized. Concealed 
randomization will be executed by the UMGCCC Pharmacist. Data on eligible consented cases 
will be submitted electronically on the appropriate on-study form to the pharmacy, where the 
participant is randomized to imatinib or placebo. The randomized treatment allocations use 

32 
 
stratified, permuted block randomization with a variable block size; blocks are generated using a 
validated random number generator. 
 
10.2. 
Primary endpoint  
 
The primary endpoint is all-cause mortality at Day 28 after the start of imatinib/placebo.   
 
10.3. 
Sample size estimation and power 
 
Group sample sizes of 173 in Arm A and 173 in Arm B achieve 80% power to detect a 
difference between the mortality in the two trial arms of 0.10. The proportion in Arm A (imatinib 
treatment arm) is assumed to be 0.10 under the null hypothesis and 0.20 under the alternative 
hypothesis. The proportion in Arm B (placebo control arm) is 0.10. The test statistic used is the 
one-sided Fisher's Exact Test. The significance level of the test is targeted at 0.05. The 
significance level actually achieved by this design is α=0.0385. The power of the test is calculated 
using binomial enumeration of all possible outcomes 
The sample size is not inflated for dropouts. All participants will be evaluable irrespective 
of the clinical course of their disease. The primary analysis will be conducted using an intention to 
treat principle (ITT) for participants who at least receive one dose of study drug or placebo. The 
sample size is not inflated for dropouts.. 
 
10.4. 
Secondary endpoints 
 
1) all-cause mortality at Day 60 after the start of 
imatinib/placebo; 2) the proportion of patients with a two-
point improvement at Day 14 from baseline using the 8-
category ordinal scale; 3) time to a 2-point clinical 
improvement difference over baseline; 4) duration of 
hospitalization; 5) duration of ECMO or invasive mechanical 
ventilation (for participants who are on ECMO or mechanical 
ventilation at Day 1); 6) duration of ICU stay (for 
participants who are in ICU at Day 1); 7) proportion of 
participants with negative oropharyngeal or nasopharyngeal 
swab for SARS-CoV-2 by quantitative RT-PCR on days 14 
and 28 after starting treatment; 8) proportion of participants 
with serious adverse events; 9) proportion of participants 
who discontinue study drug due to adverse events. 
 
10.5. 
Interim analysis 
 
No interim analysis for efficacy is planned. All grade 
4 and 5 toxicities will be reported within 24 hours to an 
independent DSMB. The DSMB will decide if early stopping 
due to unacceptable toxicity is necessary. 
 
10.6. 
Safety profile 
 
A full safety profile will be reported with severity graded according to CTCAE, attribution 
to treatment, duration and time to resolution of toxicity. The safety population consists of all 
individual who received at least one dose of study medication. 
 
10.7. 
Analysis of Efficacy Endpoints 
 
Efficacy endpoint will be analyzed using the 1-sided Fisher’s Exact Test. Response rates 
and the difference in response rates between trial arms will be estimated with 95% CI. 
8-category ordinal scale  
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 

33 
 
11. CORRELATIVE SCIENTIFIC STUDIES 
 
11.1. 
Viral Shedding  
 
Viral shedding will be determined by testing eluate from oropharyngeal or nasopharyngeal 
swab using RT-PCR). The swabs will be stored at -80oC until use. Each sample will be tested in 
duplicate according to established protocol for SARS-CoV-2 in a CLIA-certified laboratory. Per 
FDA recommendation, “we will consider conducting genotypic resistance testing to examine the 
ability of SARS-CoV-2 to develop resistance to the study drugs when viral rebound is observed 
during the study. Regions including the receptor binding domain and the S1/S2 proteolytic 
cleavage sites in the S protein of SARS-CoV-2 may be of interest.” 
 
11.2. 
Peripheral blood collection  
 
Approximately 30-50 ml of peripheral blood (if possible) at different time points per Study 
Calendar will be acquired by phlebotomy. PBMC will be isolated. The plasma will be stored at -
80oC. Cytokine response will be evaluated using Cytokine & Chemokine 34-Plex Human 
ProcartaPlex™ Panel 1A (ThermoFisher Scientific, Cat#EPX340-12167-901). A Luminex® 200 
Instrument (LX-200) will be used to measure the cytokine concentration in plasma. Per FDA 
recommendation, we will try to determine SARS-CoV-2 RNA in collected blood samples. 
 
11.3. 
Serology 
 
Plasma will be used to determine the anti-SARS-Cov2 spike protein IgG and IgM levels 
by ELISA as well as IL-6. Purified spike protein will be coated in 96-well plates and incubated 
with serial dilution of participant plasma. As negative control plasma from pre-COVID-19 healthy 
individuals will be used. The antibodies will be detected using HRP-conjugated anti-hu-IgG and 
IgM antibodies followed by TMB reagent. The dilution at which the signal is reduced by 50% 
compared to maximum signal will be reported as EC50. 
 
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