Clinical trial NCT05057221
Conditions: COVID-19 Pneumonia
Keywords: Uproleselan Selectin Inhibitor
Sponsor: Lena Napolitano, MD
Start date: 2021-11-12; Completion date: 2022-03-09
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out whether the drug uproleselan can help patients with severe COVID-19 pneumonia. Investigators will study both the side effects of the drug and assess if the drug will help patients recover more quickly and slow down the progression of acute respiratory failure.

Detailed description:
Soluble E-selectin is a significant biomarker for adult respiratory distress syndrome (ARDS). Soluble E-selectin also has pro-inflammatory properties further releasing cytokines and promoting its synthesis and the continued influx of neutrophils. Small molecule glycomimetic antagonists of E-selectin (rivipansel and uproleselan) are 500- to 1000-fold more potent inhibitors of E-selectin and have shown activity and no measurable toxicity in human clinical trials for other indications. Treatment with these E-selectin inhibitors reduced the levels of soluble E-selectin in the bloodstream which occurs during recovery of ARDS. Thus, antagonists of E-selectin which include glycomimetic antagonists and more specifically, rivipansel (GMI-1070) and uproleselan (GMI-1271), may be used to treat COVID-19 patients with respiratory symptoms that may lead to ARDS

Primary Objective:

Safety of uproleselan in patients with severe COVID-19 pneumonia.

Secondary Objectives:

To evaluate if treatment with uproleselan administered intravenously in addition to the best available therapy according to institutional guidelines is able to reduce the progression of acute respiratory failure, in patients with severe COVID-19 pneumonia.

* To evaluate proportion of patients alive and free of respiratory failure through Day 28
* To evaluate overall survival and all-cause mortality at day 15 and 28.
* To evaluate changes in the COVID ordinal outcomes scale.
* To assess adverse events to evaluate the safety of uproleselan.
* To assess ventilator-free days, ICU-free days, oxygen, vasopressor free days.
* To evaluate changes in D-dimer.

Exploratory Objectives:

* To examine the correlation of plasma soluble E-selectin concentrations with clinical outcomes.
* To examine the correlations of other biomarkers of interest with clinical outcome.

Previous versions of this record mistakenly suggested the trial would assess the number of participants who experienced a Grade 3-5 hemorrhagic event. The outcome title has been corrected to state the number of participants with a Grade 3-4 hemorrhagic event were assessed, as the scale used does not go to Grade 5.

Arms: arm 1: Uproleselan injection is a sterile solution for IV administration, supplied in single-dose vials at a concentration of 50 mg/mL.
Interventions: intervention 1: Uproleselan
Intervention descriptions: intervention 1: Uproleselan 20 mg/kg BID up to maximum dose of 2500 mg, infused IV over 20 minutes on days 1-7 or until hospital discharge. It should be administered intravenously (IV) into a peripheral line, a central catheter, or a peripherally inserted central line catheter (PICC). Infusion should take place at a steady rate over a period of 20 minutes ±2 minutes using a syringe pump or IV pump.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
1 
 
 
 
 
A Pilot Study to Assess the Safety, Tolerability and Efficacy of Selectin 
Inhibitor Uproleselan (GMI-1271) in Patients with COVID-19 Pneumonia 
 
NCT05057221 
 
IRB approval 7/1/2022 
 
 
 
 


 
 
2 
 
 
 
A Pilot Study to Assess the Safety, Tolerability and Efficacy of Selectin Inhibitor Uproleselan (GMI-
1271) in Patients with COVID-19 Pneumonia 
 
 
Principal Investigators: 
Lena M. Napolitano, MD, FACS 
Director, Surgical Critical Care 
Department of Surgery, 1C340-UH, SPC 5033 
1500 East Medical Center Drive 
Ann Arbor, MI 48109-5033 
Telephone: 734-615-4775 
Email:lenan@umich.edu 
 
Suman Sood, MD 
University of Michigan Hemophilia and Coagulation Disorders 
Program 
Division of Hematology/Oncology 
C351A Med Inn 
Telephone: 734-615-2681 
Fax: 734-763-7672 
Email: sumisood@med.umich.edu 
 
Co-Investigator(s): 
 
Thomas Wakefield, MD 
Department of Surgery/Section of Vascular Surgery 
Andrea Obi, MD 
Department of Surgery/Section of Vascular Surgery 
Study Drug: 
Uproleselan (GMI-1271) injection, 50 mg/mL 
Version 
10 (June 2022) 
 
 
 
 
 


 
 
3 
 
TABLE OF CONTENTS  
 
 
 
 
 
 
 
      
     2 
LIST OF TABLES 
4 
ABBREVIATIONS 
5 
STUDY SCHEMA 
9 
STUDY SYNOPSIS 
10 
1 
BACKGROUND AND RATIONALE 
13 
1.1 
COVID-19 Pneumonia and ARDS Disease Background 
13 
1.2 
Selectins and COVID-19 Background 
14 
1.3 
Study Agent(s) Background and Associated Known Toxicities 
17 
1.4 
Rationale 
22 
1.5 
Correlative Studies/Special Studies 
23 
2 
STUDY OBJECTIVES 
24 
2.1 
Primary Objective 
24 
2.2 
Secondary Objectives 
24 
3 
ENDPOINTS 
 
24 
3.1 
Primary Endpoints 
24 
3.2 
Secondary Endpoints 
24 
4 
SUBJECT ELIGIBILITY 
25 
4.1 
Inclusion Criteria 
26 
4.2 
Exclusion Criteria 
26 
5 
SUBJECT SCREENING AND ENROLLMENT PROCEDURES 
27 
5.1 
Treatment Dosage and Administration 
27 
5.1.1 Treatment Plan 
27 
5.1.2 Evaluating for Progression to Acute Respiratory Failure 
27 
5.2 
Assessment for Toxicities 
28 
5.3 
Concomitant Medications/Treatments 
29 
5.4 
Duration of Therapy 
29 
5.5 
Duration of Follow-Up 
30 
5.6 
Off Study Criteria 
30 
5.7 
Subject Replacement 
30 
6 
STUDY PROCEDURES 
30 
6.1 
Screening Procedures 
31 
6.1.1    Procedures during Study Drug Treatment Visits 
31
 
 
 


 
 
4 
 
6.2 
Study Schedule of Events 
32 
7 
MEASUREMENT OF EFFECT 
33 
7.1 
Safety/Tolerability 
33 
7.2 
Efficacy 
33 
8 
ADVERSE EVENTS 
33 
8.1 
Experimental Therapy 
33 
8.2 
Definitions 
34 
8.2.1 Adverse Event Reporting Requirements 
34 
8.2.2 Serious Adverse Events 
35 
8.2.3 Expected Adverse Events 
36 
8.2.4 Unexpected Adverse Events 
36 
8.3 
Adverse Event Characteristics 
36 
8.3.1 CTCAE Term 
36 
8.3.2 Attribution of the AE 
36 
8.4 
Serious Adverse Event Reporting Guidelines 
37 
8.4.1 Principal Investigators Should be Notified of any Serious Adverse Events 
38 
8.5 
Routine Reporting 
39 
8.6 
Reporting of Unanticipated Problems 
39 
8.7 
Pregnancies 
39 
9 
   DRUG INFORMATION 
40 
9.1 
Uproleselan Injection, 50 mg/mL 
40 
10 
CORRELATIVES/SPECIAL STUDIES  
 
 
   
 
 
   43 
10.1 Sample Collection Guidelines 
43 
10.2 Assays to be Performed on Samples 
43 
10.3 Assay Methodology 
43 
11 
SPECIMEN BANKING 
 
 
 
 
 
   
 
 
   43 
12 
STATISTICAL CONSIDERATIONS 
 
 
 
   
 
 
   44 
12.1 Study Design/Study Endpoints 
44 
12.2 Sample Size and Accrual 
45 
12.3 Data Analyses Plans 
45 
13 
STUDY STOPPING RULES 
 
 
 
 
   
 
 
   46 
14 
DATA AND SAFETY MONITORING 
 
 
 
   
 
 
   47 
15 
REFERENCES 
 
 
 
 
 
 
   
 
 
   48
 
 


 
 
5 
 
LIST OF TABLES 
 
Table 1: WHO Ordinal Scale Ordinal Score                                                                                               25, 45 
Table 2:  Description of Treatment 
27 
Table 3:  Standard of Care Treatments                                                                                                        28 
Table 4:  Events of the Study 
32 
Table 5:  Parameters to be Tested for Hematology, Serum Chemistry, and Coagulation Studies 
33 
Table 6:  Definition of AEs 
37
 
 


 
 
6 
 
ABBREVIATIONS 
 
AC 
Anticoagulation 
AE 
Adverse event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AT 
Antithrombin III 
AUC 
Area under the curve 
BD 
Becton, Dickinson and Company 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BT 
Bleeding time 
BUN 
Blood urea nitrogen 
C or °C 
Celsius 
Cmax 
maximum serum concentration 
Cmin 
minimum serum concentration 
CBC 
Complete blood count 
CLr 
Renal clearance 
CMP 
Comprehensive metabolic panel 
CrCl 
Creatinine clearance 
CRP 
C-reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CRF 
Case report form 
CRO 
Contract research organization 
CSM 
Clinical supply management 
CTEP 
Cancer therapy education program 
CTO 
Clinical trials office 
DLT 
Dose Limiting Toxicity 
DHEP 
di-(2-ethylhexyl) phthalate 
DNA 
deoxyribonucleic acid 
DOACs 
Direct oral anticoagulants 
DSMB 
Data and safety monitoring board 
 


 
 
7 
 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and safety monitoring plan 
DVT 
Deep vein thrombosis 
DVU 
Diagnostic Vascular Unit 
ECG 
Electrocardiogram 
ED 
Early Discontinuation 
EDTA 
Ethylenediaminetetraacetic acid 
EGFR 
Estimated Glomerular Filtration Rate 
ELISA 
Enzyme-linked immunosorbent assay 
ESL-1 
E-Selectin Ligand-1 
F or °F 
Fahrenheit 
F1.2 
Prothrombin fragment 1+2 
FDA 
Food and Drug Administration 
FSC 
Forward scattered light 
G or g 
Grams 
GCP 
Good clinical practice 
GMI 
GlycoMimetics 
H&P 
History and physical examination 
hERG 
Human ether-a-go-go related gene 
HIV 
Human immunodeficiency virus 
HSCs 
Hematopoietic stem cells 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICF 
International conference of harmonization 
ID 
Intraduodenal 
IDS 
Investigational Drug Service 
IL-6 
IL-10 
Interleukin-6 
Interleukin-10 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IP 
Intraperitoneal 
IRB 
Institutional review board 
ISTH 
International Society of Thrombosis and Hemostasis 
IU 
International unit 
IUD 
Intrauterine device 
IV or iv 
Intravenous 
KG or kg 
Kilogram 


 
 
8 
 
 
LE 
Lower extremity 
LFA-1 
Leukocyte function-associated antigen-1 
LFTs 
Liver function tests 
LMWH 
Low molecular weight heparin 
m2 
squared 
MAC-1 
macrophage-1 antigen; CD11b/CD18 
MAD 
multiple ascending dose 
MCRU 
Michigan Clinical Research Unit 
MICHR 
Michigan Institute for Clinical Studies and Health Research 
mg 
Milligrams 
MHC 
Major histocompatibility complex 
MMP 
Matrix metalloproteinase 
Min 
Minutes 
MPs 
Microparticles 
MPO 
Myeloperoxidase 
MTD 
Maximally tolerated dose 
N 
Number 
NCI 
National cancer institute 
NETs 
Neutrophil endothelial traps 
ng 
Nanogram 
NHP 
Non-human primates 
NIH 
National Institutes of Health 
NSAID 
Non-steroidal anti-inflammatory drug 
PBS 
Phosphate buffered saline 
PE 
Pulmonary embolism 
pg 
Picogram 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PMA 
Platelet monocyte aggregates 
PMNs 
Polymorphonuclear leukocytes 
PSGL-1 
P-Selectin Glycoprotein Ligand 1 
PT 
Prothrombin time 
PTS 
Post thrombotic syndrome 
QD 
Daily 
rpm 
Revolutions per minute 


 
 
9 
 
SAE 
Serious Adverse Event 
SCD 
Sickle Cell Disease 
sCD40L 
Soluble CD40L 
SDF-1 
Stromal cell-derived factor 1 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
sICAM-1 
Soluble intercellular cell adhesion molecule 1 
sLex 
SialyLewisx 
sEsel 
Soluble E-selectin 
sPsel 
Soluble P-selectin 
SQ or SC 
Subcutaneous 
SSC 
Side scattered light 
sTF 
Soluble tissue factor 
TAT 
Thrombin-Antithrombin Complex 
TCR 
TEAE 
T-cell receptor 
Treatment-emergent adverse event 
TEG 
Thromboelastography 
TF 
Tissue factor 
TNF-α 
Tumor necrosis factor 
TK 
Toxicokinetics 
Tx 
Treatment 
ULN 
Upper limit of normal 
UM 
University of Michigan 
US 
United States 
VTE 
Venous thromboembolic disease 
VEGF 
Vascular endothelial growth factor 
VTE 
Venous thromboembolic disease 
VWF 
von Willebrand factor 
WBC 
White blood cells 


 
 
10 
 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary outcome: Safety 
 
Secondary outcome: 
Assessment of reduction 
in the progression to 
acute respiratory failure  
[Time Frame: 15 and 28 
days] 
Adult, age ≥18 to ≤85 
years  
documented COVID-19 
pneumonia 
requiring supplemental 
oxygen 
requiring hospital 
admission 
enrolled ≤ 48 hours of 
hospital admission or of 
COVID-19 confirmation 
Uproleselan 20 mg/kg 
BID, up to a maximum  
of 2500 mg per dose or 
5000 mg per day 
IV over 20 minutes on 
treatment days 1-7 
 


 
 
11 
 
STUDY SYNOPSIS 
 
Title 
A Pilot Study to Assess the Safety, Tolerability and Efficacy of Selectin 
Inhibitor Uproleselan (GMI-1271) in Patients with COVID-19 pneumonia 
Phase 
Phase I (proof of concept, prospective, interventional, open label single group 
assignment) 
Methodology 
Open label with matched de-identified retrospective control cohort  
Study Duration 
Approximately 24 months 
Study Center(s) 
Single Center in the United States – University of Michigan, Ann Arbor 
Objectives 
Primary Objective:  
Safety of uproleselan in patients with severe COVID-19 pneumonia.  
Secondary Objectives: 
 
To evaluate if treatment with uproleselan administered intravenously in 
addition to the best available therapy according to institutional guidelines is 
able to reduce the progression of acute respiratory failure, in patients with 
severe COVID-19 pneumonia.  
● To evaluate overall survival and all-cause mortality at day 15 and 28. 
● To evaluate changes in the COVID ordinal outcomes scale. 
● To assess adverse events to evaluate the safety of uproleselan. 
● To assess ventilator-free days, ICU-free days, oxygen, vasopressor free 
days. 
● To evaluate changes in D-dimer. 
 
Exploratory Objectives: 
• 
To examine the correlation of plasma soluble E-selectin concentrations 
with clinical outcomes. 
• 
To examine the correlations of other biomarkers of interest with clinical 
outcome. 
Number of Subjects 
15 subjects will be enrolled in the experimental cohort to receive uproleselan. 
with 1:1 matched de-identified retrospective control cohort. (n=15) 
Inclusion Criteria 
 
 
 
 
 
 
 
 
 
 
1. Adults, ages 18 – 85 years. 
2. Willing and able to provide informed consent prior to performing study 
procedures unless they have a legally authorized representative (LAR). 
3. Documented COVID-19 pneumonia: defined as upper respiratory tract 
specimen (nasopharyngeal swab (NPS) or viral throat swab) positive for 
COVID-19 and imaging (CXR/CT scan) suggestive of COVID-19 
pneumonia. 
4. Confirmed coronavirus (SARS-CoV-2) infection, enrolled ≤ 48 hours of 
beginning oxygen need for COVID-19+ confirmed hospital admission. 


 
 
12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. Currently hospitalized requiring supplemental oxygen.  
6. Have severe COVID-19 according to the World Health Organization 
(WHO) Interim Guidance with confirmation by real-time RT-PCR assay. 
The enrollment criteria with one of the following: respiratory distress, 
respiratory rate (RR) ≥30 beats/min; oxygen saturation level less than 
93% in resting state; or partial pressure of oxygen (PaO2)/oxygen 
concentration (FiO2) ≤ 300 mmHg.  
WHO, Clinical management of severe acute respiratory infection when 
Novel coronavirus (nCoV) infection is suspected: Interim guidance. 
https://www. who.int/publications-detail/clinical-management-of-severe-
acute-respiratory-infectionwhen-novel-coronavirus-(ncov)-infection-is-
suspected.  
7. Willing and able to participate in all required evaluations and procedures.  
Exclusion Criteria 
1. In the opinion of at least one investigator, unlikely to survive for 
>48 hours from screening. 
2. Severe chronic respiratory disease (e.g. COPD or other) requiring 
supplemental oxygen and/or having required mechanical ventilation pre-
COVID-19 infection.  
3. Concurrent enrollment in a COVID-related interventional drug trial. Use 
of remdesivir, steroids, and convalescent plasma are permitted along with 
other standard of care therapies for COVID.  
4. Currently on invasive mechanical ventilation.  
5. Hypotension defined as systolic blood pressure < 90 mmHg on two 
sequential readings at least 4 hours apart.  
6. Total Bilirubin ≥ 3 x upper limit of normal (ULN), Creatinine Clearance  
≤ 30 mL/min/1.73m2. 
7. Pregnant or breastfeeding.  
8. Known diagnosis of an acute thrombosis on admission.  
9. Concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus 
anticoagulation to treat deep venous thrombosis or pulmonary embolism 
(single antiplatelet or anticoagulant agent at prophylactic dose is 
permitted).  
10. Concomitant use of thrombolytic therapy.  
11. Concomitant therapeutic systemic anticoagulant therapy (e.g. heparin, 
warfarin, direct thrombin inhibitors and direct factor Xa inhibitors).  
12. History of recent major bleeding, defined in accordance with the criteria 
of the International Society on Thrombosis and Hemostasis (ISTH).  
13. History of bleeding disorder thought to impose excessive bleeding risk, as 
per investigator discretion.  
14. Hemodynamic instability, defined as inability to maintain mean arterial 
pressure.  
15. Hypersensitivity to the active substance or to any of the excipients of 
uproleselan.  


 
 
13 
 
16. Any physical examination findings and/or history of any illness that, in 
the opinion of the investigator, might confound the results of the study or 
pose an additional risk to the patient by their participation in the study.  
Study Product(s), 
Dose, Route 
Uproleselan 20mg/kg BID, up to a maximum dose of 2500mg, IV infused 
over 20 minutes on days 1-7. 
Duration of 
Administration 
Uproleselan: 20-minute IV infusion BID on days 1-7. 
Control 
1:1 matched de-identified retrospective control cohort (patients enrolled during 
the same period with similar severity, not enrolled in another interventional 
trial, receiving best available therapy according to institutional guidelines). 
Statistical 
Methodology 
This is a pilot proof of concept feasibility study. 15 patients who consent to 
drug administration will be enrolled in the treatment arm. The sample size 
determination was not based on statistical power analysis but is large enough 
to provide adequate information regarding safety, and will contribute to the 
design of subsequent studies, and is the number of patients that we can expect 
to accrue in the current setting of the SARS-CoV2 pandemic. 
 
Descriptive statistics will be calculated for quantitative safety data, as well as 
change from baseline. Frequency counts will be compiled for classification of 
qualitative safety data.  
 
Regarding secondary endpoints, the efficacy of uproleselan in prevention of 
acute respiratory failure, the rate will be calculated as the proportion of patients 
who experienced at least one of the events above by day+15 from treatment 
start. The biomarkers will be evaluated for trends at the sample collection time 
points and contrasted graphically and with simple statistics to the levels 
observed for control cohort subjects, as the study is not powered for this 
endpoint. 


 
 
14 
 
1 BACKGROUND AND RATIONALE 
 
1.1 
COVID-19 Pneumonia and ARDS Disease Background 
 
Coronavirus Disease 2019 (COVID-19), caused by a novel coronavirus (SARS-CoV2), is a highly 
infectious pathogen that spreads primarily through respiratory droplets and/or aerosol particles. Though 
many affected patients express only mild symptomatology, with fever, cough and myalgias/fatigue, 
approximately 10-20% of patients may develop a more severe phenotype with rapid progression to acute 
respiratory distress syndrome (ARDS), septic shock, disseminated intravascular coagulation (DIC) and 
hypercoagulability. Older age and co-morbid conditions (obesity, diabetes, immunocompromised, etc.) 
are known risk factors for a more severe disease phenotype. ARDS has a very high associated mortality 
rate. 
 
ARDS causes diffuse alveolar damage in the lung.1 There is hyaline membrane formation in the alveoli in 
the acute stage, and this is followed by interstitial widening and by edema and then fibroblast 
proliferation in the organizing stage. COVID‐19 ARDS causes the typical ARDS pathological changes of 
diffuse alveolar damage in the lung.2   
 
Pulmonary thrombosis is common in COVID‐19 ARDS.3 Coagulation dysfunction appears to be 
common in COVID‐19 and is detected by elevated D‐dimer levels. In fatal cases there is diffuse 
microvascular thrombosis, suggesting a thrombotic microangiopathy, and most deaths from COVID‐19 
ARDS have evidence of thrombotic disseminated intravascular coagulation.4 This may explain some of 
the atypical or unexpected manifestations seen in the lung, such as dilated pulmonary vessels on chest 
CT, and episodes of pleuritic pain. Vascular enlargement is rarely reported in typical ARDS, yet was seen 
in most cases of COVID‐19 ARDS.5   
 
COVID‐19 ARDS appears to have worse outcomes than ARDS from other causes. The intensive care 
unit and hospital mortality from typical ARDS are 35.3% (95% CI, 33.3–37.2%) and 40.0% (95% CI, 
38.1–42.1%), respectively.6 For COVID‐19 ARDS, mortality ranged between 26% and 61.5% if ever 
admitted into a critical care setting, and in patients who received mechanical ventilation, the mortality 
can range between 65.7% to 94%. Risk factors for poor outcomes include older age; presence of 
comorbidities such as hypertension, cardiovascular disease and diabetes mellitus; lower lymphocyte 
counts; kidney injury; and raised D‐dimer levels. Death from COVID‐19 ARDS is due to respiratory 
failure (53%), respiratory failure combined with cardiac failure (33%), myocardial damage and 
circulatory failure (7%), or death from an unknown cause.7   
 
Given the high mortality rate associated with COVID-19 ARDS, preventing progression of COVID-19 
pneumonia in patients simply requiring supplemental oxygen to COVID-19 ARDS is a key priority and 
goal. 
 
 
 


 
 
15 
 
1.2     Selectins and COVID-19 Background 
 
Cell Mediated Inflammation and COVID-19 
The usual cause of death and the need for ventilator-assisted hospitalization from COVID-19 is the 
progression to ARDS, with an influx of neutrophils (PMN) into the lungs after extravasation from the 
bloodstream.  These PMNs degranulate and then release a wide variety of inflammatory mediators.  This 
results in a positive feedback loop with a further influx of PMNs, vascular leakage, fluid accumulation in 
the lungs, and impairment of oxygen exchange.  Neutrophil and platelet accumulation in the alveolar 
space results in thrombo-inflammation, and platelets trigger release of neutrophil extracellular traps 
(NETs), which have been found to correlate with alveolar-capillary and epithelial barrier disruption in 
ARDS.8  Amongst patients with severe SARS-CoV-2 viral pneumonia with progression to respiratory 
failure, serum cell-free DNA, myeloperoxidase (MPO)-DNA, and citrullinated histone H3 (Cit-H3) are 
elevated, highly specific markers of NETs.  Neutrophil counts correlate with cell-free DNA and MPO-
DNA.9  Cell-free DNA and MPO-DNA levels were higher in hospitalized patients receiving mechanical 
ventilation as compared to hospitalized patients breathing room air, suggesting that illness severity is 
associated with neutrophil response.9 
 
Additionally, in experiments performed in vitro, serum from SARS-CoV-2 infected patients triggered 
NET release from normal neutrophils.9  A retrospective case control study of hospitalized COVID-19 
patients reported that those who developed thrombosis had significantly higher blood levels of remnants 
of NETs (cell-free DNA, MPO-DNA complexes and citrullinated histone H3) and neutrophil activation 
(as evidenced by elevated calprotectin) compared to those without thrombosis, and were associated with 
levels of D-dimer.10  These data provide evidence that SARS-CoV-2 infection induces a pro-NETotic 
state amongst hospitalized patients, and these NETs could be partially responsible for the heightened 
thrombotic phenotype seen in these patients. 
 
In addition to neutrophils, pathologic studies have also demonstrated a low to moderate number of 
mononuclear cells in the lungs in COVID-19 non-survivors.11  The role they directly play is not entirely 
clear, but is likely multifactorial based on the diverse roles monocytes and macrophages (Mo/MΦ) play 
in lung physiology.  Patients may manifest a significant cytokine storm with severe COVID-19 
pneumonia that can lead to death12, 13  and many of the responsible mediators are Mo/MΦ-derived.14-16  
These include proinflammatory cytokines such as interleukin (IL)-1β, IL-8, IL-6, and type I interferons 
(IFN-I).  Direct viral infection may then promote the release from alveolar epithelial cells, alveolar 
macrophages and stromal cells of monocyte chemoattractants, resulting in a sustained recruitment of 
monocytes into the lungs.17  These monocytes then differentiate into pro-inflammatory macrophages.  
Mo/Mᴓ also activate and are activated by NK cells and T cells, further promoting this recruitment by 
granulocyte-macrophage-colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF), and 
interferon-γ (IFNγ).17, 18  In the lungs, oxidized phospholipids can accumulate and they also activate these 
Mo/Mᴓ. Virus sensing pathways such as toll-like receptor 7 (TLR7), sensing single-stranded RNA 
recognition, and Type 1 interferon may induce the expression of entry receptors allowing the virus to 
enter into the cytoplasm of the macrophages, activating the NLRP3 inflammasome.17  This leads to the 
secretion of mature IL-1β and IL-18, which amplify macrophage activation through paracrine or 


 
 
16 
 
autocrine effects.  Oxidative stress, pathogen-associated molecular patterns (PAMPs) and damage-
associated molecular patterns (DAMPs) also activate Mo/MΦ via TLR4-TRIF-TRAF6-NFκβ pathway, 
resulting in surface tissue factor expression.17, 19  Additionally, activated neutrophils and Mo/Mᴓ can 
directly bind to platelets, and these induce and amplify thrombosis. 
 
Endothelial cell dysfunction has been reported to be very important in COVID-19 associated vascular 
inflammation and coagulopathy.  Type 1 endothelial cell activation leads to the release of stored proteins 
such as P-selectin and vWF, while Type II endothelial cell activation occurs with the release of new 
proteins such as E-selectin, ICAM-1, VCAM-1, vWF, IL-1, MCP-1, and tissue factor.20  At this phase, 
the processes are reversible but if left unchecked, endothelial cell apoptosis and even endothelial cell 
necrosis can occur, resulting in the impaired microcirculatory function.  Additionally, as multiple organ 
involvement is associated with severe COVID-19 infection, endothelial cell infection has been a concern.  
Endotheliitis occurs due to viral involvement (as noted with presence of viral bodies) and the host 
inflammatory response.21  Endotheliitis could explain the impaired microcirculatory function in different 
vascular beds (including the kidneys and lungs) and their clinical sequelae in patients with COVID-19.  
Thus, a therapy that targets the endothelial cells may play an important protective role in the treatment of 
this disease.  This suggests that the E-selectin inhibitor, uproleselan (GMI-1271), may be a perfect agent 
to limit or eliminate the interactions between inflammatory cells, platelets and the endothelium, protect 
the lung and also decrease thrombosis. 
 
E-selectin as a target for COVID-19 
Soluble E-selectin is a significant biomarker for ARDS.  Soluble E-selectin also has pro-inflammatory 
properties further releasing cytokines and promoting its synthesis and the continued influx of neutrophils. 
Blocking E-selectin with the weak natural carbohydrate ligands containing sialyl Lex in an animal model 
of acute lung injury mitigated release of myeloperoxidase, permeability, and hemorrhaging.  Small 
molecule glycomimetic antagonists of E-selectin (rivipansel and uproleselan) are 500- to 1000-fold more 
potent inhibitors of E-selectin and have shown activity and no measurable toxicity in human clinical trials 
for other indications.  Treatment with these E-selectin inhibitors reduced the levels of soluble E-selectin 
in the bloodstream which occurs during recovery of ARDS.  Thus antagonists of E-selectin which include 
glycomimetic antagonists and more specifically, rivipansel (GMI-1070) and uproleselan (GMI-1271), 
may be used to treat COVID-19 patients with respiratory symptoms that may lead to ARDS or who have 
already been diagnosed with ARDS.22  Additionally, as endothelial cell infection and endotheliitis has 
been implicated as a cause of the multiple organ involvement associated with severe COVID-19, and that 
SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence 
of viral involvement (as noted with presence of viral bodies) and the host inflammatory response, a 
therapy that targets endothelial cells may play an important protective role in this disease.21  In addition, 
induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients 
with COVID-19, and COVID-19 - endotheliitis could explain the systemic impaired microcirculatory 
function in different vascular beds (including and importantly the kidneys) and their clinical sequelae in 
patients with COVID-19. 
 
In addition to neutrophils as mentioned above, pathologic studies have also demonstrated a large number 


 
 
17 
 
of mononuclear cells in the lungs in non-survivors.  So, what is the role of an E-selectin inhibitor in 
preventing the extravasation of monocytes into the tissues?  It has been shown that GMI-1271 inhibits the 
influx of inflammatory cells: Monocytes (LY-6Chi), Macrophages, Neutrophils and Myeloid cells into 
plaques,23 inflammatory monocytes (LY-6Chi) express PSGL-1 which is a risk factor for ARDS and these 
monocytes also bind the selectins,24 and the influx of neutrophils is an earlier event that may usher in an 
influx of inflammatory monocytes (LY-6Chi).25  Thus, the timing of dosing with GMI-1271 should be 
most effective at an early time point, at the initial influx of neutrophils.  E-selectin inhibition with GMI-
1271 has been found to be effective in the inhibition of the same cytokines in an animal model of G-CSF 
induced sepsis that are released in the cytokine storm of severe COVID-19 patients.12  Finally, a recent 
study from France has determined that sE-selectin is significantly increased in patients transferred into 
the ICU from the floor in COVID-19 patients admitted into the hospital.  In this study, patients age 18 or 
greater with a positive SARS-CoV-2 test and an infectious syndrome were evaluated with values of 
52,937 pg/ml in ICU patients (n20) and 37,931 in medicine patients not in the ICU (n20).26  In a 
subsequent study of 32 patients with confirmed SARS-CoV-2 infection who underwent a whole blood 
gene expression profile analysis (11 ICU and 21 non-ICU cases), critically ill COVID-19 patients had a 
significant increased expression of E-selectin normalized RNA count.26  Based on this data, an inhibitor 
to E-selectin should have efficacy in COVID-19. 
 
We have measured soluble E-selectin levels in 12 patients who survived their COVID-19 infections vs. 
12 patients who died from COVID-19 (many with multiple blood draws in each group).  We found a 
statistically significant increase in levels of soluble E-selectin of those patients who died, as compared to 
those who survived.   
 
We have also measured soluble E-selectin levels in our MM-ICU patients with COVID-19 pneumonia, 
respiratory failure and ARDS and determined that the levels are significantly increased, and that higher 
levels and increasing levels over time are associated with death (Figure below). 
 
  
 
 


 
 
18 
 
 
1.3 
Study Agent(s) Background and Associated Known Toxicities 
 
Selectins function in venous thrombosis presumably by binding and activating immune cells to initiate 
the coagulation cascade.  E-selectin (CD62E) is known to bind and activate both monocytes and 
neutrophils.  Uproleselan (GMI-1271) is a small molecule antagonist that specifically inhibits E-
selectin and is rationally designed to mimic the bioactive conformation of the sialyl-Lex carbohydrate 
ligand.  E-selectin inhibition has been tested as a therapeutic for venous thrombosis.  The 
pathophysiology of venous thrombosis has been driven by the concept of Virchow’s triad: endothelial 
injury, circulatory stasis, and blood hypercoagulability.  Inflammation was added when it was 
demonstrated that P-selectin, a glycoprotein, when inhibited decreased thrombosis in a primate AV 
fistula model. Early work suggested that both P-selectin and E-selectin were critical to the thrombotic 
process. E-selectin is also a key regulator of thrombus formation and fibrin content.  In studies using 
GMI-1271 in a stasis mouse model of IVC thrombosis, the inhibitor was equivalent to LMWH for 
limiting thrombosis, but with a marked decrease in tail vein bleeding time. 
 
Mice treated with GMI-1271 had decreased venous thrombus formation with significant inhibition at 
10mg/kg BID (P=0.0271). Treatment with LMWH significantly decreased thrombus formation 2 days 
post induction at 6mg/kg (P=0.0203). All mice pre-treated prophylactically with GMI-1271 or LMWH 
followed the same pattern of decreasing thrombus weight 2 days post injury (P<0.05).  In a second phase 
of this study, mice were administered a single bolus of saline (10 mg/kg), GMI-1271 (10mg/kg/day), or 
a therapeutic dose of LMWH (6 mg/kg/day) as predetermined by allometric scaling for mice to assess 
tail bleeding times.  In the extended single dose monkey study where monkeys were dosed 250mg/kg 
and coagulation (PT and aPTT) was tested, no test article effects were seen. LMWH at 6mg/kg dose 


 
 
19 
 
significantly elevated tail bleeding times in mice versus controls (341±27, 491±60 vs. 82±6 seconds, 
P<0.01).  GMI-1271 (10 mg/kg/day, IV) had significantly lower tail bleeding times compared to IV 
dose of LMWH (6mg/kg, p<0.01). 
 
This and other data led to a clinical study (supported by NIH VITA) in which GMI-1271 was given to 
normal volunteers in a dose-dependent fashion as a one-time dose, then as a daily dose for 5 
consecutive days compared to enoxaparin or saline, and finally to treat calf vein DVT.27  There were 
no serious adverse events, GMI-1271 did not affect thromboelastographic parameters, lower levels of 
sE-sel were found in GMI-1271 treated subjects (as expected for on-target effects), and there was 
lower leukocyte and platelet activation in GMI-1271 treated volunteers (determined by MPO and 
MAC-1 levels). Two patients with calf vein DVT were treated with GMI-1271 with a 5-day 
intravenous course. Both patients had immediate relief of pain and significant increase in vein 
recanalization by day 19. The effectiveness of GMI-1271 has been confirmed in a primate model of 
proximal iliac vein thrombosis, both inhibiting thrombosis and vein wall fibrosis (supported by NIH 
VITA).28, 29  In fact, GMI-1271 was more effective in inhibiting thrombosis and protecting again vein 
wall fibrosis than a combination of GMI-1271 plus LMWH.29 This strongly suggests that E-selectin 
has a significant role in both thrombogenesis and post-thrombotic syndrome after DVT and may be an 
excellent pharmacologic target. 
 
In a recent publication,12 Carl June and John Moore report that severe disease leading to ARDS has been 
described in up to 20% in COVID-19 cases. They further state that the pathology of disease is similar 
to cytokine-release syndrome (CRS)-induced ARDS observed in leukemia patients undergoing CAR-T 
cell therapy. CRS was also found to be the major cause of morbidity in patients infected with other 
coronaviruses such as SARS-CoV and MERS-CoV. The cytokine storm in these diseases consisted of 
the release of inflammatory cytokines such as IL1β, IL-8, IL-23 as well as IL-6.13 Monocytes and 
macrophages are targeted by SARS-CoV-2 by binding to cell surface ACE2 receptors. These cells are 
also known to contribute to the development of CRS that is observed in patients receiving CAR-T cell 
therapy. To target these cells, GM-CSF was inhibited by genetic ablation of CAR T-cells (GM-CSFk/o 
CAR-T cells) (ref. 8) which effectively reduced CRS and enhanced therapy. To simulate the effects of 
GM-CSF inducing cytokine release in patients, mice were dosed with G-CSF and inflammatory 
cytokines were measured in fluids derived from a femoral flush. Treatment of mice with uproleselan 
significantly inhibited expression of cytokines that are found in COVID-19 patients experiencing 
cytokine release syndrome (CRS).  
 
Uproleselan has been studied extensively in toxicology studies, including in multiple species (rodent 
and non-rodent).  In 91-day repeat-dose studies in mice and monkeys, the no observed effect levels 
(NOEL) was the highest doses tested, 2000 mg/kg/day in mice and 500 mg/kg/day in monkeys.  No test 
article related effects were found in the following parameters and endpoints in both species: mortality, 
clinical signs, body weights, food consumption, ophthalmology, clinical pathology parameters 
(hematology, coagulation, clinical chemistry, and urinalysis, gross necropsy findings, organ weights, or 
histopathologic examinations.  In addition, there were no findings after electrocardiographic 
examinations in monkey.  Safety pharmacology testing suggests no cardiovascular, respiratory, or 


 
 
20 
 
central nervous system (CNS) risk to humans.  Uproleselan has no known mutagenic potential.  
Therefore, continuing human studies are supported by the existing toxicology, safety pharmacology and 
genotoxicity data.  For additional information, refer to the IB. 
 
This study will be conducted under the US IND #155100. Comprehensive preclinical testing has been 
completed in advance of human clinical trials. Full details of the preclinical program can be found in 
the uproleselan Investigator’s Brochure (IB). 
 
The doses of uproleselan have been determined using pre-clinical data. The therapeutic range of 
uproleselan is believed to lie between 2 to 40 mg/kg (see uproleselan Investigator’s Brochure). 
Uproleselan is an IV formulation that has been extensively tested in humans by GMI in several studies 
in healthy volunteers, patients with calf level DVT, and patients with acute myeloid leukemia (AML) 
and multiple myeloma (MM).  
 
Uproleselan (GMI-1271) is an E-selectin antagonist. Soluble E-selectin (sE-selectin) is a significant 
biomarker for ARDS and has recently been described as biomarker for progression of disease in COVID-
19 patients (1). In a recovering COVID-19 patient the concentration of sE-selectin in the blood correlates 
with improvement and with other markers of COVID-19 infection (IL-6, ferritin and ACE2) as shown in 
Figure. 
 
Figure. sE-selectin correlation with clinical outcome and other biomarkers in a COVID-19 patient (ref.1) 
 
Soluble E-selectin also has pro-inflammatory properties further releasing cytokines and promoting its 
synthesis and the continued influx of neutrophils. Blocking E-selectin with the weak natural carbohydrate 
ligands containing sialyl Lex in an animal model of acute lung injury mitigated release of 
myeloperoxidase, permeability and hemorrhaging.  Small molecule glycomimetic antagonists of E-
selectin (Rivipansel and Uproleselan) are 500- to 1000-fold more potent inhibitors of E-selectin and have 
shown activity and no measurable toxicity in human clinical trials for other indications.   
 
Treatment with these E-selectin inhibitors reduced the levels of soluble E-selectin (sE-selectin) in the 
bloodstream of patients in these 2 different clinical trials. A dose of 10mg/ml was chosen based on scaled 


 
 
21 
 
doses from efficacy animal models of AML and blood levels corresponding to IC90 values of uproleselan 
for E-selectin determined in assays.  The effects of dosing uproleselan (10mg/kg) with treatment of AML 
patients on circulating sE-selectin levels is shown in Figure below - there is a significant drop in soluble 
E-selectin levels over time, up to 200 hours. 
 
Figure.  Uproleselan decreases blood concentrations of sEselectin in AML patients.   
Nagy B. Jr. et.al. A dramatic rise in serum ACE2 activity in a critically ill COVID-19 patient. Int. J. Inf. 
Disease 103: 412-414 (2021) 
In our clinical study performed in normal volunteers and in patients with calf vein DVT, we found levels 
of soluble E-selectin to be a good marker for on-target effects of GMI-1271, and lower levels of soluble 
E-selectin were found in daily GMI-1271-treated volunteers after 4 days.27 Thus, we wish to follow the 
decrease in soluble E-selectin levels as a means to determine the efficacy of uproleselan treatment. In a 
recent publication, reduction of soluble E-selectin in COVID-19 patients correlated with improved 
prognosis. Soluble E-selectin was found to be a marker for severity in COVID-19 patients and predicts 
those who will need to go to the ICU for more intensive care as opposed to those who did not progress to 
ICU-level care. 44 Thus, the antagonist of E-selectin, uproleselan (GMI-1271), may be used to treat 
COVID-19 patients with respiratory symptoms that may lead to ARDS or who have already been 
diagnosed with ARDS.  Additionally, as endothelial cell infection and endotheliitis have been implicated 
as a cause of the multiple organ involvement associated with severe COVID-19, and that SARS-CoV-2 
infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral 
involvement (as noted with presence of viral bodies) and the host inflammatory response, a therapy that 
targets endothelial cells may play an important protective role in this disease.  These data strongly 
suggest that E-selectin may be an excellent pharmacologic target to reduce progression to ARDS in 
patients with acute COVID-19 pneumonia. 
                    
Given the severe acute nature of COVID-19 and the clear relationship of patient outcome to soluble E-


 
 
22 
 
selectin levels, a dose at the higher end of 40 mg/kg range of doses evaluated in healthy volunteers was 
desired to exert a strong pharmacological effect with minimal safety risk for this acute severe 
inflammatory event.  In addition to the precedented exposure in healthy volunteers, the 20 mg/kg dose 
selected for this trial is equivalent to the highest dose tested in AML patients in study GMI-1271-
201.   Thus, this dose level has precedent in both healthy volunteers and patients with advanced cancer.    
 
In addition to human exposure, uproleselan has been extensively studied in non-clinical toxicology 
studies, including 91-day repeat dose studies.  The NOEL from 91-day repeat dose studies in mice and 
cynomolgus monkeys is 2000 mg/kg and 500 mg/kg, respectively.  These non-clinical dose levels 
provide a 5-fold mean safety margin compared the exposure expected from a 20 mg/kg human dose.       
 
Furthermore, exposure response analyses demonstrated that safety and efficacy responses are not 
dependent on exposure over the range of exposures attained in the GMI-1271-201 trial, which 
administered dose levels of 5, 10 and 20 mg/kg Q12h.  Pharmacokinetic analysis of study GMI-1271-201 
revealed dose related increases in exposure and, importantly, dose related increases in the time above 
IC50 and IC90 for E-selectin.   
 
The 20 mg/kg dose level selected for this trial provides COVID-19 patients optimal exposures to 
maximize the time that uproleselan remains above the E-selectin inhibitory concentration level and the 
potential pharmacologic response while remaining within the range of doses already evaluated in 
humans. 
 
In summary, a 20 mg/kg dose for the COVID-19 trial was selected in order to provide a safe dose, within 
the range of doses already evaluated in humans, and to provide uproleselan exposures sufficient to ensure 
a pharmacologic effect in a single arm trial.   
 
To date, 189 subjects who have received uproleselan are included in the integrated safety analyses (86 
healthy volunteers and 103 subjects with AML, MM, or DVT). 
The majority of subjects (114/189) have received uproleselan 10 mg/kg. A total of 86 subjects 
received at least 1 dose of uproleselan in the healthy volunteer studies. 
Ten subjects received 2 mg/kg uproleselan, 22 received 5 mg/kg, 32 received 10 mg/kg, 
13 received 20 mg/kg, 4 received 40 mg/kg, and 5 subjects received 800 mg uproleselan. 
Refer to uproleselan Investigator’s Brochure for a summary of TEAEs with incidence ≥10% (very 
common) reported for all treated subjects in the healthy volunteer studies of uproleselan. Overall, 49 
subjects (49/86, 57.0%) experienced at least 1 TEAE. Incidence rates were similar among dose 
groups. 
 
TEAEs were most frequently reported in the System Organ Classes (SOCs) of nervous system 
disorders (23/86 subjects, 26.7%), musculoskeletal and connective tissue disorders (17/86,19.8%), and 
general disorders and administration site conditions (16/86 subjects, 18.6%).  Overall, the most 
frequently reported TEAEs were headache (19/86 subjects, 22.1%), back pain (15/86, 17.4%), and 
infusion site pain (9/86 subjects, 10.5%).  No nonserious TEAEs with a severity Grade ≥3 were 


 
 
23 
 
reported in any of these healthy volunteer trials. 
 
In studies of uproleselan in subjects with AML, MM, and DVT, 103 subjects received 
uproleselan and are included in the safety analyses (91 in the AML study, 10 in the MM study, and 2 
in the DVT study). The majority of subjects received uproleselan 10 mg/kg (82/103), while 13/103 
received 5 mg/kg uproleselan and 8/103 received 20 mg/kg uproleselan.  Refer to uproleselan 
Investigator’s Brochure for a summary of TEAEs with incidence ≥10% (very common) reported for 
all treated subjects in these studies.  
Overall, 100 subjects (100/103, 97.1%) experienced at least 1 TEAE. Incidence rates were similar 
among dose groups.  TEAEs were most frequently reported in the SOCs of gastrointestinal disorders 
(91/103 subjects, 88.3%), general disorders and administration site conditions (82/103, 79.6%), blood 
and lymphatic system disorders (77/103, 74.8%), metabolism and nutrition disorders (71/103, 68.9%), 
and respiratory, thoracic and mediastinal disorders (57/103 subjects, 55.3%). 
 
Overall, the most frequently reported TEAEs for subjects who have received uproleselan (101 of 
whom received uproleselan in addition to their chemotherapy regimens) were diarrhea (69/103 
subjects, 67.0%), febrile neutropenia (60/103, 58.3%), nausea (59/103, 57.3%), fatigue (47/103, 
45.6%), decreased appetite (40/103, 38.8%), constipation (36/103, 35.0%), hypokalemia (36/103, 
35.0%), edema peripheral (35/103, 34.0%), chills (33/103, 32.0%), and vomiting (32/103 subjects, 
31.1%). 
 
Refer to uproleselan Investigator’s Brochure for a summary of treatment-emergent SAEs for all 189 
subjects who have received uproleselan (101 of whom received uproleselan in addition to their 
chemotherapy regimens) in clinical trials. To date, 36 subjects have experienced at least 1 SAE 
(36/189 subjects, 19.0%). Eight of 35 subjects (8/35, 22.9%) who received 5 mg/kg uproleselan, 
25/114 subjects (21.9%) who received 10 mg/kg uproleselan, and 3/21 subjects (14.3%) who received 
20 mg/kg uproleselan experienced at least 1 SAE during their participation in clinical studies. No 
SAEs have occurred in the 19 subjects dosed with 2 mg/kg, 40 mg/kg, or 800 mg uproleselan. 
 
Across all studies, the only SAEs reported for >2% of subjects were febrile neutropenia 
(7/189 subjects, 3.7%), sepsis (5/189, 2.6%), and pneumonia (4/189 subjects, 2.1%). Only 
1 SAE was reported in the healthy volunteer studies (unrelated Grade 2 muscular weakness). (Refer to 
the uproleselan IB for further information).  
 
 
1.4 
Rationale/ Novelty 
 
Uproleselan is an E-selectin antagonist. Soluble E-selectin is a significant biomarker for ARDS.  
Soluble E-selectin also has pro-inflammatory properties further releasing cytokines and promoting its 
synthesis and the continued influx of neutrophils. Blocking E-selectin with the weak natural 
carbohydrate ligands containing sialyl Lex in an animal model of acute lung injury mitigated release of 
myeloperoxidase, permeability, and hemorrhaging.  Small molecule glycomimetic antagonists of E-


 
 
24 
 
selectin (Rivipansel and Uproleselan) are 500- to 1000-fold more potent inhibitors of E-selectin and 
have shown activity and no measurable toxicity in human clinical trials for other indications.  
Treatment with these E-selectin inhibitors reduced the levels of soluble E-selectin in the bloodstream 
which occurs during recovery of ARDS.  Thus antagonist of E-selectin Uproleselan (GMI-1271) may 
be used to treat COVID-19 patients with respiratory symptoms that may lead to ARDS or who have 
already been diagnosed with ARDS.22  Additionally, endothelial cell infection and endotheliitis have 
been implicated as a cause of the multiple organ involvement associated with severe COVID-19 and 
SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct 
consequence of viral involvement (as noted with presence of viral bodies) and the host inflammatory 
response. Therefore, a therapy that targets endothelial cells may play an important protective role in 
this disease.21  This strongly suggests that E-selectin may be an excellent pharmacologic target to 
reduce progression to ARDS in patients with acute COVID-19 pneumonia. 
 
Endothelial injury is an underlying mechanism that links inflammation and thrombosis in severe 
COVID-19.  The combination of elevated selectin levels, high VWF levels, microvascular thrombosis, 
and microvascular inflammation all suggest that microvascular injury may be a common trigger for 
both the inflammatory and thrombotic complications of COVID-19.  E-selectin levels were 
significantly increased in COVID-19 patients requiring hospitalization from ED (pdf attached).   
Inhibitors of endothelial exocytosis may represent a novel therapeutic approach to the vasculopathy of 
COVID-19. Inhibition of selectin would block part of the pathway downstream of endothelial injury, 
including leukocyte rolling and platelet adherence to the vessel wall. We have also measured soluble 
E-selectin levels in our MM-ICU patients with COVID-19 pneumonia, respiratory failure and ARDS 
and determined that the levels are significantly increased, and that higher levels and increasing levels 
over time are associated with death (Figure above). 
 
1.5 
Correlative Studies/Special Studies 
 
Biomarkers to evaluate the effects of Uproleselan 
The measurement of biomarkers of coagulation, inflammation and angiogenesis in subjects exposed to 
uproleselan vs. standard of care will enable us to evaluate the effect of Uproleselan on the progression 
of acute respiratory failure in patients with severe COVID-19 pneumonia.  The biomarkers chosen 
will be indicators of disease severity and progression as well as drug efficacy. 
Currently there is no single biomarker that can specifically detect venous thrombosis or its associated 
inflammatory response in patients. Ramacciotti et al have demonstrated the usefulness of combining 
circulating biomarkers of coagulation and inflammation to determine a clinical profile that can exclude or 
confirm if a patient has DVT.30 Therefore in this application we will determine if the previously measured 
biomarkers which include D-dimer as a measure of clot production and breakdown and are significantly 
elevated in COVID-19 infection and correlate with disease severity;31-33 soluble E-selectin (E-selectin 
specifically shown to have highly elevated levels in COVID-19 positive patients transferred into the ICU)26 
and soluble P-selectin, which are essential glycoproteins expressed during clot formation; Interleukin-6 
(IL-6) and interleukin-10 (IL-10) which are cytokines involved with systemic inflammation that rise with 


 
 
25 
 
venous thrombosis and potential players in the cytokine storm phenomenon at play in COVID-19 patients 
experiencing ARDS.  The 4-day change in IL-6:IL-10 ratio, chosen to derive the Dublin-Boston score, was 
associated with more severe outcomes with COVID-19;34 Angiopoietin-2, an angiogenic growth factor 
affecting cardiovascular remodeling and indicator of endothelial cell activation shown to be predictive of 
severe COVID-19 infection,26, 35 and TNF-alpha an acute phase proinflammatory cytokine which may be 
another indicator of disease severity during COVID-19 infection.36  
 
2.   STUDY OBJECTIVES 
 
2.1 
Primary Objective 
To determine the safety of uproleselan in patients with severe COVID-19 pneumonia.  
 
2.2    Secondary Objectives 
 
To evaluate if treatment with uproleselan administered intravenously in addition to the best available 
therapy according to institutional guidelines is able to reduce the progression of acute respiratory failure, 
in patients with severe COVID-19 pneumonia.  
 
 
● To evaluate overall survival and all-cause mortality at day 15 and 28. 
● To evaluate changes in the COVID ordinal outcomes scale. 
● To assess adverse events to evaluate the safety of uproleselan. 
● To assess ventilator-free days, ICU-free days, oxygen, vasopressor free days. 
● To evaluate changes in D-dimer. 
 
Exploratory Objectives: 
• 
To examine the correlation of plasma soluble E-selectin concentrations with clinical outcomes. 
• 
To examine the correlations of other biomarkers of interest with clinical outcome. 
 
3.   ENDPOINTS 
 
3.1     Primary Endpoints: Safety of uproleselan in patients with severe COVID-19 pneumonia. 
 
3.2 
Secondary Endpoints 
 
 
● Reduction in the progression to acute respiratory failure [Time Frame: 15 days for primary 
endpoint].  
● Patients with a baseline PaO2/FiO2 >= 200: progression of respiratory failure is defined by:  
       a. severe gas transfer deficit (PaO2/FiO2 < 200);  
       b. persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use of 
           accessory respiratory muscles, paradoxical respiratory movements);  
 ● 
The rate will be calculated as the proportion of patients who experienced at least one of the     
events above by day+15 from treatment start. 
 


 
 
26 
 
 
• 
Reduction in the progression to acute respiratory failure [Time Frame: 28 days].  
• 
Overall survival and all-cause mortality (day 15, day 28). 
• 
Time to improvement in oxygenation for at least 48 hours. Improvement in oxygenation is 
defined as an increase in PaO2/FiO2 of 50 (or greater) compared to the nadir of PaO2/FiO2. 
• 
Number of patients requiring mechanical ventilation, if not on mechanical ventilation at study 
entry. 
• 
Change in the WHO COVID-19, “8-point ordinal scale” from study entry to day 28 (Table 1). To 
be assessed on day 3, day 8, day 15, day 28. 
• 
Duration of hospitalization and duration of ICU care. 
• 
Toxicity assessment (including incidence of grade 3-5 hemorrhagic events). 
• 
Change in D-dimer [Time Frame: baseline, study day 3, day 8, day 15, and day 28]. Changes in 
plasma D-dimer level compared with baseline at enrollment.  
• 
Decrease or Change in IL-6:IL-10 ratios.    
• 
Free-Days- at day 28 
Oxygen 
Ventilator 
Vasopressor 
ICU 
Hospitalization 
 
 
 Table 1: WHO Ordinal Scale Ordinal Score 
  
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Endpoints 
 
● Soluble E-selectin and P-selectin levels compared with baseline at enrollment. 
● Thrombosis free days (clinically defined) at day 28. 
● Change in other cytokine levels, endothelial or leukocyte activation (day 1, 15, 28) in IL-6, IL-
10, Angiopoietin-2, and TNF-alpha 
 
 
4. SUBJECT ELIGIBILITY 
 
Patients with confirmed severe COVID-19 pneumonia admitted to hospital, requiring 
supplemental oxygen. Subjects must meet all of the inclusion and none of the exclusion criteria 
to be enrolled in the study. Study treatment may not begin until a subject is enrolled. 
 


 
 
27 
 
4.1    Inclusion Criteria 
 
1. Adults, ages 18-85 years.   
2. Willing and able to provide informed consent prior to performing study procedures unless they have a 
legally authorized representative (LAR). 
3. Documented COVID-19 pneumonia: defined as upper respiratory tract specimen (nasopharyngeal swab 
(NPS) or viral throat swab) positive for COVID-19 and/or imaging at computed tomography scan 
suggestive of COVID-19 pneumonia.  
4. Confirmed coronavirus (SARS-CoV-2) infection admitted to the hospital, enrolled ≤ 48 hours of need for 
supplemental oxygen.  
5. Currently hospitalized requiring supplemental oxygen.  
6. Have severe COVID-19 according to the WHO Interim Guidance with confirmation by real-time RT-
PCR assay. The enrollment criteria with one of the following: respiratory distress, RR ≥30 beats/min; 
oxygen saturation level less than 93% in resting state; or partial pressure of oxygen (PaO2)/oxygen 
concentration (FiO2) ≤ 300 mmHg.  
WHO, Clinical management of severe acute respiratory infection when Novel coronavirus (nCoV) 
infection is suspected: Interim guidance. https://www. who.int/publications-detail/clinical-management-
of-severe-acute-respiratory-infectionwhen-novel-coronavirus-(ncov)-infection-is-suspected.  
7. Willing and able to participate in all required evaluations and procedures. 
 
4.2     Exclusion Criteria 
 
1. In the opinion of at least one investigator, unlikely to survive for >48 hours from screening. 
2. Severe chronic respiratory disease (e.g. COPD or other) requiring supplemental oxygen and/or having 
required mechanical ventilation pre-COVID-19 infection.  
3. Concurrent enrollment in a COVID related interventional drug trial. Use of remdesivir, steroids, and 
convalescent plasma are permitted along with other standard of care therapies for COVID.37  
4. Currently on invasive mechanical ventilation.  
5. Hypotension defined as systolic blood pressure < 90 mmHg on two sequential readings at least 4 hours 
apart. 
6. Total Bilirubin ≥ 3 x upper limit of normal (ULN), Creatinine Clearance ≤ 30 mL/min/1.73m2.   
7. Pregnant or breastfeeding.  
8. Known diagnosis of an acute thrombosis on admission.  
9. Concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus anticoagulation to treat deep 
venous thrombosis or pulmonary embolism (single antiplatelet or anticoagulant agent at prophylactic 
dose is permitted).  
10. Concomitant use of thrombolytic therapy.  
11. Concomitant therapeutic systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin 
inhibitors and direct factor Xa inhibitors). As per NIH Guidelines: Hospitalized adults with COVID-19 
should receive VTE prophylaxis per the standard of care for other hospitalized adults (AIII). 
Anticoagulant or antiplatelet therapy should not be used to prevent arterial thrombosis outside of the 
usual standard of care for patients without COVID-19 (AIII); 
https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/ 
12. History of recent major bleeding, defined in accordance with the criteria of the International Society on 
Thrombosis and Hemostasis (ISTH).  
13. History of bleeding disorder thought to impose excessive bleeding risk as per investigator discretion  
14. Hemodynamic instability, defined as inability to maintain mean arterial pressure.  
15. Hypersensitivity to the active substance or to any of the excipients of uproleselan. 
16. Any physical examination findings and/or history of any illness that, in the opinion of the investigator, 
might confound the results of the study or pose an additional risk to the patient by their participation in 
the study 


 
 
28 
 
5. 
SUBJECT SCREENING AND ENROLLMENT PROCEDURES 
 
Patients who present to the University of Michigan Health System who have confirmed severe 
COVID-19 pneumonia admitted to hospital, requiring supplemental oxygen will be recruited. The 
study research team will contact the potential subject to discuss the study in detail and review the 
informed consent document. Prior to any study-specific screening evaluations and clinical trial 
participation, written informed consent will be obtained from each potential subject or legally authorized 
representative (LAR) in the clinical trial using the Institutional Review Board (IRB) approved informed 
consent form (ICF). Potential subjects will be informed in detail about the study products to be 
administered, and the nature of the clinical investigation. The subjects will also be informed that they 
are free to withdraw their consent and discontinue their participation in the clinical trial at any time. 
Each subject will be given a copy of the signed ICF. 
 
5.1 
Treatment Dosage and Administration 
 
Protocol treatment must start within 48 hours of the admitted patient requiring supplemental oxygen for 
documented COVID-19 pneumonia.  Study enrollment is defined as the day subject meets all of the 
inclusion criteria and none of the exclusion criteria. 
 
5.1.1 Treatment Plan 
 
Up to 15 subjects will be enrolled in this prospective, interventional, single-arm, open label trial.  
All drug administration will be performed by nurses in the inpatient unit. Uproleselan injection is a sterile 
solution for IV administration, supplied in single-dose vials at a concentration of 50 mg/mL. Uproleselan 
should be administered intravenously (IV) into a peripheral line, a central catheter, or a peripherally 
inserted central line catheter (PICC).  Infusion should take place at a steady rate over a period of 20 minutes 
±2 minutes using a syringe pump or IV pump.  Microbore tubing is preferred. In-line filtration is highly 
recommended. Dilution of uproleselan may be performed with normal saline (0.9% Sodium Chloride) up 
to 5x as needed for ease of administration and per institutional practice. Compatibility with other 
therapeutic agents has not been determined, therefore uproleselan should not be administered concurrently 
with anything other than saline.  When flush is used, saline flush is preferred. 
 
 
Table 2: Description of Treatment 
Agent 
Premedications/ 
Precautions 
Dose 
Route 
Schedule 
Uproleselan 
(GMI-1271) 
None 
20 mg/kg BID, 
up to a 
maximum dose 
of 2500 mg 
IV 
infusion 
over 20 
min 
Daily on 
treatment days 
1-7 
 
 


 
 
29 
 
Table 3: Standard of Care Treatments 
1.  Supplemental oxygen, escalate to heated high flow nasal cannula, noninvasive ventilation, endotracheal 
intubation and mechanical ventilation as needed. 
2.  Conservative fluid management strategy. 
3.  Dexamethasone 6mg (PO or IV) qD for up to 10d (RECOVERY trial, Horby PW et al.38 
4.  Remdesivir 200 mg loading dose, then100 mg daily for up to 9 additional days (ACTT-1 Study, Beigel 
JH et al.).39 
5. Convalescent plasma for compassionate use. 
6. Other medical management as recommended by Infectious Disease Consultants. 
7.  Management of septic shock. 
8.  ICU admission as required. 
 
 
5.2 
Assessment for Toxicities 
 
Any subject who receives treatment on this protocol will be evaluable for toxicity.  Each subject will be 
assessed for the development of toxicity according to the Time and Events Table (Table 3). Toxicity 
will be assessed according to the CTCAE v. 5. 
 
All drug administration will be performed by nurses in the inpatient unit. Routine vital sign 
measurement will be performed and all adverse events (AEs) will be recorded. Toxicities will be 
classified as AEs probable, possible, unlikely or unrelated to uproleselan. 
 
5.2.1 
Evaluating for progression to Acute Respiratory Failure 
 
● Reduction in the progression to acute respiratory failure [Time Frame: 15 days].  
● Patients with a baseline PaO2/FiO2 >= 200: progression of respiratory failure is defined by:  
       a. severe gas transfer deficit (PaO2/FiO2 < 200).  
       b. persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use 
     of accessory respiratory muscles, paradoxical respiratory movements).  
● The rate will be calculated as the proportion of patients who experienced at least one of the 
events above by day+15 from treatment start.  
• 
Overall survival and all-cause mortality (day 15, day 28). 
• 
Time to improvement in oxygenation for at least 48 hours. Improvement in oxygenation is 
defined as an increase in PaO2/FiO2 of 50 (or greater) compared to the nadir of PaO2/FiO2. 
• 
Number of patients requiring mechanical ventilation, if not on mechanical ventilation at study 
entry. 
• 
Change in the WHO COVID-19, “8-point ordinal scale” from study entry to day 28 (Table 1). To 
be assessed on day 3, day 8, day 15, day 28. 
• 
Duration of hospitalization and duration of ICU care. 
• 
Toxicity assessment (including incidence of grade 3-5 hemorrhagic events). 
• 
Change in D-dimer [Time Frame: baseline, study day 3, day 8, day 15, and day 28]. Changes in 
plasma D-dimer level compared with baseline at enrollment.  
• 
Decrease or Change in IL-6:IL-10 ratios.    


 
 
30 
 
• 
Free-Days- at day 28 
Oxygen 
Ventilator 
Vasopressor 
ICU 
Hospitalization 
Table 1: WHO Ordinal Scale Ordinal Score 
 
 
 
 
 
                   
      
Exploratory Endpoints 
● Soluble E-selectin and P-selectin levels compared with baseline at enrollment. 
● Thrombosis free days (clinically defined) at day 28. 
● Change in other cytokine levels, endothelial or leukocyte activation (day 1, 15, 28) in IL-6, IL-
10, TNF-alpha and Angiopoietin-2. 
 
5.3 
Concomitant Medications/Treatments 
 
             Table 3: Standard of Care Treatments40 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.4 
Duration of Therapy 
 
Each subject in the treatment arm will receive one dose of uproleselan every 12 hours (12 hours apart 
optimally; acceptable range 10-14 hours) on treatment days 1-7. 
1.  Supplemental oxygen, escalate to heated high flow nasal cannula, noninvasive ventilation, 
endotracheal intubation and mechanical ventilation as needed. 
2.  Conservative fluid management strategy. 
3.  Dexamethasone 6mg (PO or IV) qD for up to 10d (RECOVERY trial, Horby PW et al. 38 
4.  Remdesivir 200 mg loading dose, then100 mg daily for up to 9 additional days (ACTT-1 
Study, Beigel JH et al. 39 
5. Convalescent plasma for compassionate use. 
6. Other medical management as recommended by Infectious Disease Consultants. 
7.  Management of septic shock. 
8.  ICU admission as required. 


 
 
31 
 
5.5 
Duration of Follow-Up 
 
Subjects will be followed for 28 days. Subjects with treatment-emergent adverse events will be followed 
until resolution or stabilization of the adverse event. 
 
5.6 
Off Study Criteria 
 
Subjects can be taken off study at any time at their own request, or they may be withdrawn at the 
discretion of the investigator for safety, behavioral, or administrative reasons. If possible, subject will 
follow protocol procedures related to safety analysis. The reason(s) for discontinuation from study will 
be documented and may include: 
• 
Subject withdraws consent (termination of treatment and follow-up). 
• 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment and follow-up. 
• 
Subject is unable to comply with protocol requirements. 
• 
Treating physician judges continuation on the study would not be in the subject’s 
best interest. 
• 
Drug-related toxicity or adverse event, which contraindicates continuation in the study 
• 
Subject becomes pregnant: If patient pregnancy results become known during treatment 
period, pregnancy should be followed and specific monitoring as per NIH guidelines 
conducted.41   
• 
Termination of the study by The University of Michigan or GlycoMimetics Inc. 
• 
Subject completes protocol treatment and follow-up criteria. 
 
 
5.7 
Subject Replacement 
 
Subjects will be replaced in this study if they are removed. 
 
6 
STUDY PROCEDURES 
 
6.1 
Screening Procedures 
 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Hematology, serum chemistry or coagulation assessments performed for 
clinical indications will be used from hospital admission. All screening procedures, unless noted above, 
must be performed within 48 hours of subject’s requirement of supplemental oxygen for diagnosis of 
COVID pneumonia and prior to enrollment unless otherwise stated. The screening procedures include: 
 
• 
Informed Consent 
• 
Demographics 
• 
Age, gender, race, ethnicity 
• 
Complete medical and surgical history 
• 
Review subject eligibility criteria 
• 
Review and record prior and concomitant medications/therapies 
• 
Physical exam including vital signs, height and weight 


 
 
32 
 
Vital signs include temperature, pulse, respirations, blood pressure 
• 
Hematology, serum chemistry and coagulation studies 
• 
Serum pregnancy test (for females of child-bearing potential) 
 
6.1.1 
Procedures during Study Drug Treatment Visits 
 
If a laboratory parameter has been obtained within 48 hours prior to study enrollment, it does not need to 
be repeated for study purposes and will be considered the *baseline* value. Following the last day of study, 
no further “study related” blood tests will be obtained. 
 
Guidelines for monitoring hematologic and coagulation parameters were derived from Thachil, J., et al., 
ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb 
Haemost, 2020. 18(5): p. 1023-1026.42 
 
• 
Pulmonary Indices: Pulmonary parameters will be recorded daily for subjects from the time of 
study entry to cessation of study drug therapy. Pulmonary assessment will include a subject’s 
current level of supplemental oxygen support (%FiO2), current modality of support (mechanical 
ventilation, BiPaP, CPAP, nasal cannula, or none), and the results of any chest radiographs (if 
performed) that day. For patients that remain hospitalized on day 15 or 28 of study, pulmonary 
indices will also be made at that time point. Blood gas values will be obtained as clinically 
indicated. Scoring from the WHO COVID Ordinal Scale (Table 1) will be determined as indicated 
by study investigators or study coordinators. 
 
• 
Hematologic parameters: 
A complete blood count including platelets (CBCP) should be obtained at baseline (study entry), 
and daily until cessation of study therapy. Additional blood counts may be obtained as clinically 
indicated. 
 
• 
Chemistries: 
Serum chemistries (Electrolytes, BUN, creatinine, liver panel) should be obtained at baseline 
(study entry), and daily until cessation of study therapy. Additional chemistries should be obtained 
as clinically indicated. 
 
• 
Coagulation Labs: 
D-dimer, Prothrombin time (PT), activated partial thromboplastin time (aPTT), and serum 
fibrinogen should be obtained at baseline (study entry). Additional D-dimer, PT, and serum 
fibrinogen testing may be obtained as clinically indicated. 
 
• 
Serologic Cytokine Profiles: Biomarkers will be drawn on day 0-1 pre-study drug administration, 
days 1-7, day 15, and day 28. These will be used to measure e-selectin levels and are not for safety 
labs. Due to current hospital understaffing, blood draws will occur as staffing permits. Missed 
blood draws will not be counted as protocol deviations. 
 
 
6.2       Study Schedule of Events 
 


 
 
33 
 
Table 4: Events of the Study 
 
Baseline 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
15 
Day 
28 
Eligibility 
screen 
X 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
CBC 
Xa 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chemistries 
Xa 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ABG 
Xa 
 
 
 
 
 
 
 
 
 
 
CXR 
Xb 
 
 
 
 
 
 
 
 
 
 
Biomarkers g 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
D-dimer g 
X 
 
 
X 
 
 
 
 
X 
X 
X 
Serum 
pregnancy test 
Xc 
 
 
 
 
 
 
 
 
 
 
Pulmonary 
indicesd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Uproleselan 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signse 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
COVID scale 
X 
 
 
X 
 
 
 
 
X 
X 
X 
AE and follow-
upf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Key: CBC-complete blood count; CXR-chest X ray; ABG-arterial blood gas; BP-blood pressure; HR-heart 
rate; RR-respiratory rate. 
 
Notes: 
a. 
Laboratory tests performed within 48 hours prior to study enrollment do not need to be repeated 
at baseline.  CBC should be performed daily (until cessation of study therapy) and should be 
viewed as standard medical care. Arterial blood gas (ABG) measurements, and chest 
radiographs should be performed per routine medical care. Venous blood gas may be used when 
ABG unavailable. Patients should continue to have laboratory tests performed (as indicated 
above) until cessation of study therapy. 
b. 
Chest X-Ray (CXR): The CXR does not need to be repeated at baseline, if a CXR was done on 
admission and revealed bilateral infiltrates. 
c. 
Pregnancy test: Perform in subjects of child-bearing potential, if not already performed this 
admission for clinical care reasons. 
d. 
Pulmonary indices will be recorded daily until cessation of drug therapy, and again at day 8, 15 
and 28 (if a patient remains hospitalized at that time). Patients who are discharged prior to day 
15 or 28 do not need to have pulmonary indices assessed on day 15 or 28. 
e.  
Vital signs: heart rate, respiratory rate, blood pressure prior to and upon completion of each 
infusion.  
f.  
Adverse Event Reporting and Follow-up: Patients will be assessed for adverse events daily 
during receipt of study therapy, and for 7 days following completion of study drug therapy, 
provided they remain hospitalized during this 7-day post-therapy period. In addition, patients will 
be contacted on day 15 and 28 (±2 days), to assess their clinical status and any active adverse 
events at that time. This final assessment can be done virtually, by telephone or electronically 
(email) if the patient cannot be contacted by phone. No in-person visit is required. 
g.  
Study blood draws, including D-dimer and biomarkers, will only occur if patient is still hospitalized 
and as hospital staffing permits (weekends/holidays may not be feasible). No outpatient study 
blood draws will be performed. 
Table 5: Parameters to be Tested for Hematology, Serum Chemistry, and Coagulation Studies 
 


 
 
34 
 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume 
(MCV), platelets, mean platelet volume, red blood cells (RBCs), white blood 
cells (WBCs) with complete differential including neutrophils, lymphocytes, 
monocytes, basophils, eosinophils, immature granulocytes 
Serum chemistry 
Comprehensive metabolic panel (CMP) to include: total protein, albumin, 
alkaline phosphatase, ALT/SGPT, AST/SGOT, total bilirubin, BUN, creatinine, 
estimated glomerular filtration rate (EGFR) (ml/min), electrolytes (sodium, 
potassium, calcium, chloride, bicarbonate), and glucose 
Coagulation 
Prothrombin time (PT), international normalized ratio (INR), activated 
partial thromboplastin time (aPTT), fibrinogen 
7 MEASUREMENT OF EFFECT 
 
7.1 
Safety/Tolerability 
 
AE assessment will be performed for all subjects. The study will use the Common Terminology Criteria 
for Adverse Events (CTCAE) 5. Physical examination, vital signs, laboratory tests will be performed. 
Vitals will be taken 10-30 minutes before/after infusion OR at the closest time points possible if not 
possible in the 10-30 minute period. 
 
7.2 
Efficacy 
Reduction in the progression to acute respiratory failure [Time Frame: 15 days]  
 
Patients with a baseline PaO2/FiO2 >= 200: progression of respiratory failure is defined by:  
a. severe gas transfer deficit (PaO2/FiO2 < 200) 
b. persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use of accessory 
respiratory muscles, paradoxical respiratory movements) 
The rate will be calculated as the proportion of patients who experienced at least one of the events above 
by day+15 from treatment start.  
 
8 ADVERSE EVENTS 
 
8.1 
Experimental Therapy 
For the most recent safety update, please refer to the current uproleselan IB. 
 
 
Contraindications: 
• 
Hypersensitivity to uproleselan or related products 
• 
Interaction with other medications 
• 
Adverse Reactions 
Please refer to Section 6.2 for details; these will be reported during the study. 
8.2 
Definitions 
 


 
 
35 
 
8.2.1 Adverse Event Reporting Requirements 
 
Purpose: Adverse event data collection and reporting, which are required as part of every clinical trial, 
are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. 
 
Adverse Event Reporting: 
The descriptions and grading scales used in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. The 
CTCAE v5.0 mapping document can be downloaded at the CTEP website: 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference
_5x7.pdf) 
 
Reporting requirements may include the following considerations: 1) the characteristics of 
the adverse event including the grade (severity); 2) the relationship to the study therapy 
(attribution); and 3) the prior experience (expectedness) of the adverse event. 
 
Adverse events (AE) refer to any untoward medical occurrence associated with the use of 
an intervention in humans, whether or not considered intervention-related (21 CFR 312.32 
(a)). By way of example and without limitation, an AE can be any unfavorable and 
unintended sign (for example, an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the Study Drug. 
 
Protocol-defined and serious AE will be collected for 28 days following the first study drug dose, or 
death, whichever comes first. In addition, patients with drug related AE will be monitored until 
symptom resolution, even if the symptoms extend beyond the 28-day period. 
 
AEs may include: 
• 
Exacerbation (i.e., an increase in the frequency or severity) of a pre-existing 
condition. Illness present before study entry should be recorded in the medical history 
section of the CRF and only be reported as an AE if there is an increase in frequency 
or severity of the condition during the study. 
• 
Intercurrent illnesses with an onset after administration of study drug begins. 
 
AEs DO NOT include: 
• 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment is considered to be pre-existing in nature. Any known pre-existing 
conditions that are ongoing at time of study entry should be considered medical 
history. 
• 
Medical or surgical procedures (the condition that leads to the procedure is the AE) 
• 
Situations where an untoward medical occurrence has not taken place. For example: 
- Planned hospitalizations due to pre-existing conditions, which have not worsened. 
- Hospitalizations that occur for procedures not due to an AE. 
- Hospitalization for the diagnostic procedure where the hospital stay is less than 24 
hours in duration or for normal management procedures (i.e. chemotherapy). 
 
Laboratory findings DO NOT need to be reported as AEs in the following cases: 
• 
Laboratory parameters already beyond the reference range at screening. 
• 
Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (e.g., in vitro hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
• 
An abnormal laboratory value that cannot be confirmed after repeat analysis, 


 
 
36 
 
preferably in the same laboratory. 
 
 
8.2.2 
Serious Adverse Events 
All serious adverse events (SAEs) regardless of causality to study drug, will be reported 
to the Principal Investigator within 24 hours of first awareness of the event. Follow-up 
information must also be reported within 24 hours of receipt of the information by the 
investigator. 
 
All SAEs will be reported to the IRB per current institutional standards. In this trial, serious, 
unexpected adverse events believed to be definitely, probably or possibly related to the 
study treatment will be reported to the Food and Drug Administration via the MedWatch 
3500A. The Michigan IND/IDE Assistance Program (MIAP) will assist the Sponsor in 
submitting SAEs to the FDA that meet the reporting requirements in 21 CFR 312.32. 
 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of Federal 
Regulations (CFR), Chapter 21, special procedures will be followed. All serious event reporting will 
adhere to 21 CFR 312.32 for Investigational New Drugs (IND) and to the Guidance for Industry and 
Investigators: Safety Reporting Requirements for INDs and BA/BE, dated December 2012. The 
institutional review board (IRB) will be notified of the Alert Reports as per FDA regulations. 
 
A serious adverse event (SAE) is any adverse event or suspected adverse reaction that in the view of 
either the investigator or sponsor, results in any of the following outcomes: 
• 
Death  
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
Is a congenital anomaly/birth defect and/or is an important medical event that may not result in 
death, be life-threatening, or require hospitalization but may be considered serious when, based 
upon appropriate medical judgment, may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the above definition.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization or the development of drug dependency or drug abuse. 
 
Life-threatening is defined as an adverse event or suspected adverse reaction in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does 
not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
 
Note that hospitalizations for the following reasons should not be reported as SAEs: 
 
• 
Previously planned (prior to signing the informed consent form) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the course 
of the study. 
• 
Preplanned hospitalizations or procedures for preexisting conditions that are already 
recorded in the subject’s medical history at the time of signing informed consent form 
should not be considered SAEs. 
• 
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study therapy or other protocol-required procedure) 


 
 
37 
 
should not be considered SAEs. However, if the preexisting condition worsened during the 
course of the study it should be reported as an SAE. 
 
8.2.3 Expected Adverse Events 
 
An adverse event (AE) is considered “expected” if: 
 
• 
For approved and marketed drugs or devices, those adverse events are described in 
the approved Package Insert (Label). 
• 
For investigational new drugs or devices, those adverse events are described in the IB. 
 
8.2.4 Unexpected Adverse Events 
 
Unexpected is defined as an adverse event or suspected adverse reaction that is not listed in the IB or 
Package Insert (Label) or is not listed at the specificity or severity that has been observed; or is not 
consistent with the risk information described in the general investigational plan or elsewhere in the 
current application, as amended. 
8.3 
Adverse Event Characteristics 
 
8.3.1 CTCAE Term 
 
(AE description) and grade: The descriptions and grading scales found in the National Cancer Institute 
(NCI) CTCAE version 5 will be utilized for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE version 5. A copy of the CTCAE version 5 can be downloaded from the 
Cancer Therapy Education Program (CTEP) web site. 
(http://ctep.cancer.gov;https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_5x7.pdf).  
 
If CTCAE grading does not exist for an AE, the PI is responsible for assigning a severity of mild, 
moderate, severe, and life-threatening, corresponding to Grades 1 to 4, as defined here: 
• 
Mild: The AE is of little concern to the subject. The event is not expected to have any 
effect on the subject’s health or well-being. 
• 
Moderate: The subject has enough discomfort to cause interference with or change in usual 
activities. The event is of some concern to the subject’s health or well-being. The event may 
require medical intervention. 
• 
Severe: The subject is incapacitated and unable to work or participate in many or all usual 
activities. The event is of definite concern to the subject and/or poses substantial risk to the 
subject’s health or well-being. The event is likely to require medical intervention and/or close 
follow-up. 
• 
Life-threatening: life-threatening consequences; urgent intervention indicated. 
 
 
 
8.3.2 Attribution of the AE 
 
The investigator or co-investigator listed on the 1572 is responsible for assignment of attribution.  The 
relationship of each AE to the study drug will be assessed using the following definitions: 
Table 6: Definitions of AEs 


 
 
38 
 
Term 
Definition 
Related 
Probable The AE is likely related to the study drug. The temporal relationship between 
the event and the administration of the study drug is compelling, and/or follows 
a known or suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, concomitant therapies, or 
accident. 
Possible 
The AE may be related to the study drug. There may be some temporal 
relationship between the event and the administration of the study drug but 
there remains some ambiguity as to the cause. 
Unrelated 
Unlikely The AE is doubtfully related to the study drug. The current knowledge or 
information about the AE indicates that a relationship to the study drug is 
unlikely. 
Unrelated The AE is clearly NOT related to the study drug. The event can be readily 
explained by other factors such as the subject’s underlying medical condition, 
concomitant therapy, or accident and no obvious temporal relationship exists 
between the investigational product and the event. 
 
For the purposes of this study, ‘Related’ shall mean ‘Probable’ and ‘Possible’ relationship to drug as 
determined by the PI. 
 
In the absence of information on causality from the reporting investigator, the Sponsor will consult the 
reporting investigator and encourage an opinion on this aspect. 
The outcome of the AE may be classified as follows: 
 
• 
Resolved: The subject has fully recovered from the event with no residual effects 
observable. 
• 
Resolved with sequelae: The subject has fully recovered from the event with residual 
effects observable. 
• 
Ongoing: Effects of the event are present and changing. The event is not considered 
stabilized or resolved. 
• 
Death: The event was the primary cause of death (may or may not be the immediate 
cause of death). 
Once an AE is detected, it should be followed until its resolution, and assessment should be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
study drug, interventions required to treat it, and the outcome. 
 
8.4 
Serious Adverse Event Reporting Guidelines 
 
All serious adverse events (SAEs) regardless of causality to study drug, will be reported 
to the Principal Investigator within 24 hours of first awareness of the event. Follow-up 
information must also be reported within 24 hours of receipt of the information by the 
investigator. 
 
All Serious Adverse Events will be reported to the IRB per current institutional standards. 


 
 
39 
 
 
In this trial, serious, unexpected adverse events believed to be definitely, probably or possibly related 
to the study treatment will be reported to the Food and Drug Administration via the MedWatch 3500A. 
The Michigan IND/IDE Assistance Program (MIAP) will assist the Sponsor in submitting SAEs to the 
FDA that meet the reporting requirements in 21 CFR 312.32. 
 
The original copy of the SAE Report Form and the fax confirmation sheet or email must be kept with 
the subject documentation at the study site. Follow-up information should be sent using a new SAE 
Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the 
original report. Each re- occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, and whether the subject 
continued or withdrew from trial participation. 
 
 
Reporting to GlycoMimetics, Inc. 
As the holder of the IND for the Study, University of Michigan Sponsor-Investigator, Lena Napolitano, 
MD will be responsible for all required regulatory reporting obligations and will submit IND Safety 
Reports to the FDA in accordance with applicable laws and regulations. 
 
Reports will be submitted to GlycoMimetics, Inc. by the following guidelines: 
• 
Sponsor-Investigator will send a final copy of all Suspected Unexpected Serious Adverse Reaction 
(SUSAR) reports (i.e., IND Safety Reports) to GlycoMimetics, Inc. in parallel to submission to FDA. 
• 
Sponsor will send a final copy of all Serious Adverse Event reports to GlycoMimetics, Inc. within 15 
days of Sponsor awareness of the event. 
• 
All SAE and SUSAR reports will be e-mailed to IQVIA Biotech: Safety-inbox.biotech@iqvia.com 
 
Any additional information pertaining to the SAE and SUSAR, including complications, progression of 
the initial event, and recurrent episodes, will be reported as follow-up to the original episode. 
 
8.4.1 Principal Investigators Should be Notified of any Serious Adverse Events 
 
Lena M. Napolitano, MD, FACS 
Director, Surgical Critical Care 
Department of Surgery, 1C340-UH, SPC 5033 
1500 East Medical Center Drive 
Ann Arbor, MI 48109-5033 
Telephone: 734-615-4775 
Email:lenan@umich.edu 
 
Suman Sood, MD 
University of Michigan Hemophilia and Coagulation Disorders Program  
Phone: 734-615-2681 
Pager: 17132 
Email: sumisood@med.umich.edu 


 
 
40 
 
 
8.5 
Routine Reporting 
 
All other adverse events, such as those that are expected, or are unlikely or unrelated to the drugs 
administered, are to be reported to the IRB annually as part of regular data submission. 
 
8.6 
Reporting of Unanticipated Problems 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse event) that 
may represent an unanticipated problem, the investigator should assess whether the incident, 
experience, or outcome represents an unanticipated problem. The incident, experience, or outcomes 
is considered unanticipated if it meets all of the following criteria: 
 
• 
Unexpected (in terms of nature, severity, or frequency); 
• 
Related or possibly related to participation in the research; and 
• 
Suggests that the research places subjects or others at a greater risk of harm than was 
previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an unanticipated 
problem, the investigator must report it to the IRB within 14 calendar days of the study team 
becoming aware of the problem. 
 
8.7 
Pregnancies 
 
Pregnancy occurring in a female subject or a male subject’s partner during the trial period will be 
documented in the subject’s source documents and reported on a Pregnancy Form to the SAE hotline 
and to the IRB by the investigational staff within 1 working day of their knowledge of the event.  
Pregnancy itself is not an AE; it should be reported for tracking purposes. The PI or designee will 
discontinue the pregnancy subject from the treatment aspects of the trial, continue to follow her per 
protocol for safety outcomes only, and advise her to seek prenatal care and counseling from her primary 
care provider. Data on fetal outcome and breast-feeding will be collected for regulatory reporting and 
drug safety evaluation. 
 
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation. 
 
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs/SAEs. 
 
The study staff will request the pregnant subject to notify the study site of the outcome of the pregnancy 
(i.e., birth, loss or termination). To help ensure this, the study site clinical staff will follow-up with the 
subject until the end of pregnancy, with the subject’s consent. This request and the subject’s response 
will be documented in the subject’s source document. 
 
 
9 
DRUG INFORMATION 


 
 
41 
 
 
9.1 Uproleselan Injection, 50 mg/mL 
 
Other Names for the Drug: GMI-1271 
Description: Uproleselan injection is a sterile solution for IV administration, supplied in single-dose 
vials at a concentration of 50 mg/mL. 
Classification - Type of Agent: small molecule E-selectin antagonist 
Mode of Action: E-selectin antagonist 
 
Pharmacokinetics: PK evaluations in healthy volunteers showed a dose-linear relationship in mean PK 
parameters after IV infusion of uproleselan 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, and 40 mg/kg. 
Uproleselan is characterized by a half-life of 1.4 to 2.5 hours and does not accumulate after doses up to 
20 mg/kg twice daily. Population PK analysis in healthy volunteers and subjects with AML 
demonstrates similar PK profiles, PK parameters, and dose-proportionality. Clearance was found to 
depend on renal function and have a similar magnitude in both healthy volunteers and in subjects with 
AML. Clearance is not dependent on body size which allows for flat-fixed dosing. The PK of 
uproleselan does not appear to be affected when co-administered with chemotherapy. Uproleselan is 
predominantly (>95%) excreted unchanged in the urine and is not extensively metabolized in humans. 
Refer to the uproleselan IB for further information. 
 
Side Effects: No adverse events were seen during pre-clinical testing. The safety and efficacy of 
uproleselan have not been fully established. However, limited human safety information is available 
from Phase 1 clinical trials in healthy volunteers and subjects with DVT, MM, and a Phase 1/2 clinical 
trial in subjects with AML. No specific toxicities, or target organs for toxicity, have been identified thus 
far in nonclinical studies or in clinical trials for uproleselan. This includes administration alone or with 
cytarabine-based chemotherapy regimens for AML. In healthy volunteer studies, no trends in routine 
lab evaluation such as hematology, chemistry, coagulation, urinalysis, electrocardiogram (ECG) and 
bleeding time were observed. Clinical trials are ongoing. Refer to the uproleselan IB for further 
information. 
 
Drug Interactions: No known drug interactions 
 
Uproleselan (GMI-1271) Supply and Storage 
Uproleselan must be received by designated staff at the trial site, handled and stored safely and properly, 
and kept in a secured location to which only the designated staff (i.e., pharmacist) have access.  Upon 
receipt, uproleselan should be stored frozen according to the instructions specified on the labels and in 
the IB and pharmacy reference manual. 
The investigator must not store uproleselan at, nor dispense it from, any location other than that agreed 
upon with the sponsor and approved by the IRB. 
The lot numbers for the supplied uproleselan will be provided to the trial site with the trial drug shipment.  
Uproleselan batch certificates are available at the request of site personnel. 


 
 
42 
 
Uproleselan (GMI-1271) Packaging and Labeling 
GlycoMimetics will provide uproleselan to the pharmacist in labeled containers.  Vials containing 
uproleselan will be packed into cartons containing a specific number of vials per carton.  A tamper-
evident seal will be placed on each carton.  All vial and carton labels will meet applicable local 
regulatory requirements. 
Uproleselan (GMI-1271) Preparation, and Administration 
Uproleselan injection 50 mg/mL is stored per the specified conditions on the label, frozen (-10 °C to -25 
°C), prior to administration.  The frozen product can appear as a homogenous solid, a striated solid, or as 
a super-cooled liquid.  When using frozen supply, vials should be brought to room temperature before 
dose preparation.  Upon thawing, the product should be gently inverted 4 to 5 times to ensure 
homogeneity of the solution.  The thawed solution is clear, colorless to slightly yellow, and free from 
visible particulates. 
Uproleselan should be administered IV into a peripheral line, a central catheter, or a peripherally inserted 
central line catheter (PICC).  Infusion should take place at a steady rate over a period of 20 minutes (±2 
minutes) using a syringe pump or IV pump.  Microbore tubing is preferred. In-line filtration is highly 
recommended.  Dilution of uproleselan may be performed with normal saline (0.9% Sodium Chloride) up 
to 5X as needed for ease of administration and per institutional practice.  Compatibility with other 
therapeutic agents has not been determined; therefore, uproleselan injection should be administered via a 
separate IV line and should not be administered concurrently with anything other than saline.  If a flush is 
used, saline flush is preferred. 
When prepared in syringes or intravenous (IV) bags without an administration set attached, uproleselan 
may be stored refrigerated up to 72 hours prior to administration or up to 24 hours at controlled room 
temperature prior to administration.  Administration sets manufactured from materials of construction 
other than polyvinyl chloride (PVC) with di(2-ethylhexyl)phthalate (DEHP) can be primed up to 72 
hours before dosing if stored refrigerated or up to 24 hours before dosing if stored at controlled room 
temperature.  Intravenous lines consisting of PVC with DEHP should be avoided when possible.  If PVC 
with DEHP administration sets must be used, they should be primed with uproleselan solution no more 
than 2 hours before dosing.  It is highly recommended that uproleselan prepared prior to administration 
be refrigerated until 1 hour prior to dosing.    
Uproleselan will be administered intravenously to the subject by authorized site personnel only.  It is 
critical that both the start and end times of uproleselan administration are accurately recorded in the site 
records when possible and available. 
Uproleselan is to be kept in a locked and secured storage facility, accessible only to those individuals 
authorized by the principal investigator (PI). 
 
Clinical Supply Accountability  


 
 
43 
 
The investigator and trial staff will be responsible for the accountability of all clinical supplies 
(dispensing, inventory, and record keeping) following instructions in the pharmacy reference manual and 
adhering to Good Clinical Practice (GCP) guidelines. 
Under no circumstances will the investigator and trial site staff allow the uproleselan to be used other 
than as directed by this protocol.  Uproleselan will not be dispensed to any individual who is not enrolled 
in the trial. 
An accurate and timely record of clinical supplies must be maintained.  This includes but may not be 
limited to: (a) documentation of receipt and condition of uproleselan, (b) documentation of uproleselan 
dispensing/return to/from pharmacy, and (c) documentation of destruction/return of uproleselan to 
GlycoMimetics (or designee).  All uproleselan must be accounted for and all discrepancies investigated 
and documented appropriately. 
If required, at trial close-out and as appropriate during the course of the trial, the investigator will return 
all unused uproleselan, packaging, labels, and a copy of the completed accountability logs to the 
GlycoMimetics (or designee) for drug return or destruction.   
 
Uproleselan (GMI-1271) Disposal and Destruction 
Upon written approval, and after accountability has been confirmed, the unused supply of uproleselan 
can be destroyed at the trial site per local guidelines, by a third party, or returned to the GlycoMimetics’ 
designee as appropriate. 
Misuse, Overdose, and Medication Error  
Misuse, overdose, or medication errors (as defined below) must be reported to the sponsor according to 
the SAE reporting procedure whether or not they result in an AE/SAE as described in Section 8   
Note: The 24-hour reporting requirement for SAEs does not apply to reports of investigational medicinal 
product unless these result in a SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category. 
Misuse – Intentional use of investigational medicinal product other than as directed or indicated at any 
dose.   
Overdose – Intentional or unintentional intake of a dose of an investigational medicinal product 
exceeding a pre-specified total daily dose of the investigational medicinal product.  The adverse 
experiences associated with the overdose should be reported as other serious reactions. 
Overdose will be defined as: 
• 
Total administered over a 24-hour period: >5500 mg 
Medication Error – An error made in prescribing, dispensing, administration, and/or use of an 
investigational medicinal product. 
Distribution Site: 


 
 
44 
 
 
CSM Holdings Inc. 
342 42nd St S   
Fargo, ND 58103 
 
10 CORRELATIVES/SPECIAL STUDIES 
 
10.1 Sample Collection Guidelines  
 
The total volume of plasma needed for the assays listed below is 1ml (in one 2.7 ml sodium citrate 
vacutainer tube).  The blood will be spun down at 2500xg for 20 minutes at 4degrees C, and then the 
plasma snap frozen in liquid nitrogen and then stored at -80degrees C. 
 
10.2 Assays to be Performed on Samples 
 
TNF-alpha 
soluble E-selectin  
soluble P-selectin 
Interleukin-6 (IL6) 
Interleukin-10 (IL-10)  
Angiopoietin-2 
 
Blood will be collected only via direct venipuncture at the time points delineated in Section 
6.2: Study Schedule of Events 
 
10.3 Assay Methodology 
 
Commercial ELISA assays will be used to evaluate TNF-alpha, soluble E-selectin, soluble P-selectin, 
Interleukin-6 (IL-6), Interleukin-10 (IL-10), TNF-alpha and Angiopoietin-2.  
 
Whole blood will be drawn and centrifuged based on company protocols.26, 43 Plasma will be drawn off, 
aliquoted, snap frozen, and stored at −80°C. Biomarkers analyzed by ELISA for protein determination 
include soluble E-selectin (Ebiosciences, now Thermo Fisher Scientific, Waltham, MA, USA); soluble P-
selectin, interleukin-10, interleukin-6, TNF-alpha and angiopoietin-2 (Thermo Fisher Scientific, Waltham, 
MA, USA). ELISA assays will be performed using centrifuged citrated blood according to protocol. 
Samples will be run in duplicate according to manufacturer’s instructions. 
 
11 SPECIMEN BANKING 
 
Subject samples collected for this study will be retained at the Conrad Jobst Vascular Research 
Laboratory. Samples may be used for additional testing of the Correlative/Special Studies as feasible 
with plasma remaining after all testing is complete. Any data obtained from the use of clinical specimens 
will be the property of the University of Michigan and GMI for publication and any licensing agreement 
will be strictly adhered to. 
12 STATISTICAL CONSIDERATIONS 


 
 
45 
 
 
12.1 Study Design/Study Endpoints 
 
This is a prospective, interventional, single-arm, open label trial, with 1:1 matched de-identified 
retrospective control cohort. Study subjects will receive uproleselan IV BID x 7 days. 15 patients 
who consent to drug administration will be enrolled in the treatment arm. 
 
Primary Endpoints: Safety 
 
12.1.2. Additional Interim Safety Assessment (Study Sample Size: 15 patients)  
An interim assessment for toxicity and early mortality will be performed after the first 5 patients have enrolled, 
and again after the first 10 patients are enrolled. Accrual may proceed to a maximum of 15 patients, if the 
stopping rules are not met within the first 5 patients. 
 
 
12.1.3. Secondary Endpoints 
 
● Reduction in the progression to acute respiratory failure [Time Frame: 15 days]  
● Patients with a baseline PaO2/FiO2 >= 200: progression of respiratory failure is defined by:  
       a. severe gas transfer deficit (PaO2/FiO2 < 200);  
       b. persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use of 
accessory respiratory muscles, paradoxical respiratory movements);  
The rate will be calculated as the proportion of patients who experienced at least one of the 
events above by day+15 from treatment start. 
• 
Overall survival and all-cause mortality (day 15, day 28). 
• 
Time to improvement in oxygenation for at least 48 hours. Improvement in oxygenation is 
defined as an increase in PaO2/FiO2 of 50 (or greater) compared to the nadir of PaO2/FiO2. 
• 
Number of patients requiring mechanical ventilation, if not on mechanical ventilation at study 
entry. 
• 
Reduction in progression to acute respiratory failure [Time Frame: 28 days] 
• 
Change in the WHO COVID-19, “8-point ordinal scale” from study entry to day 28 (Table 1). To 
be assessed on day 3, day 8, day 15, day 28. 
• 
Duration of hospitalization and duration of ICU care. 
• 
Toxicity assessment (including incidence of grade 3-5 hemorrhagic events). 
• 
Change in D-dimer [Time Frame: baseline, study day 3, day 8, day 15, and day 28]. Changes in 
plasma D-dimer level compared with baseline at enrollment.  
• 
Decrease or Change in IL-6:IL-10 ratios.    
• 
Free-Days- at day 28 
o Oxygen 
o Ventilator 
o Vasopressor 
o ICU 
o Hospitalization 
 
 
 
 
 
 Table 1: WHO Ordinal scale Ordinal Score: 


 
 
46 
 
  
 
 
 
Exploratory Endpoints 
 
● Soluble E-selectin and P-selectin levels compared with baseline at enrollment. 
● Thrombosis free days (clinically defined) at day 28. 
● Change in other cytokine levels, endothelial or leukocyte activation (day 1, 15, 28) in IL-6, 
IL-10, TNF-alpha and Angiopoietin-2. 
 
12.2 
Sample Size and Accrual 
 
This is a pilot proof of concept feasibility study. 15 patients who consent to drug administration 
will be enrolled in the treatment arm. 
The sample size determination was not based on statistical power analysis but is large enough to 
provide adequate information regarding safety, and to contribute to the design of subsequent 
studies, and is the number of patients that we can expect to accrue in the current setting of the 
SARS-CoV2 pandemic. 
 
12.3 Data Analyses Plans 
 
Descriptive statistics will be calculated for quantitative safety data, as well as change from baseline. Frequency 
counts will be compiled for classification of qualitative safety data.  
 
Secondary endpoints include reduction in the progression to acute respiratory failure. For patients with 
a baseline PaO2/FiO2 >= 200: progression of respiratory failure is defined by:  
       a. severe gas transfer deficit (PaO2/FiO2 < 200); 
       b. persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use of 
           accessory respiratory muscles, paradoxical respiratory movements);  
 
The rate will be calculated as the proportion of patients who experienced at least one of the events above 
by day+15 from treatment start.  
 
There are many other secondary endpoints, but two of the most important are: (i) Day 28 overall survival 
and (ii) Day 28 ventilator free survival, both of which are binary endpoints. Day 28 overall survival will 
be summarized by the proportion of the twelve patients who are alive at Day 28 after starting treatment, 
and Day 28 ventilator-free survival will be summarized by the proportion of the twelve patients who 
are both alive and not using a ventilator at Day 28 after starting treatment. Both proportions will be 


 
 
47 
 
accompanied by an exact 95% confidence interval.  All other secondary endpoints will be collected and 
assessed. 
 
 
13 STUDY STOPPING RULES 
 
Additional Interim Safety Assessment (Study Sample Size: 15 patients)  
An interim assessment for toxicity and early mortality will be performed after the first 5 patients have 
enrolled, and again after the first 10 patients are enrolled. Accrual may proceed to a maximum of 15 
patients, if the stopping rules are not met within the first 5 patients 
 
The study may be halted for further review if, for any reason involving subject safety, the PIs and 
Medical Monitors deem continuing the study inappropriate. The following scenarios will also result in 
temporarily halting the study for further review: 1) major bleeding event in more than 2 of  first 10 
patients on protocol (as defined as fatal bleeding and/or symptomatic bleeding in a critical area or organ, 
such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or 
intramuscular with compartment syndrome and/or bleeding causing a fall in hemoglobin level of 2g/dL 
or more, or leading to transfusion of two or more units of whole blood or red cells). This bleeding 
definition is congruent with International Society of Thrombosis and Hemostasis (ISTH) definition of 
major bleeding. An incidence of > 20% hemorrhagic complications would be unacceptable in this 
setting. Thus, we will continually monitor the observed proportion of patients with major bleeding 
complications. We start with prior Beta distribution, which has mean 0.2. If ever we have more than 
80% posterior probability that the true proportion is greater than 0.20, accrual to the protocol will be 
suspended to allow the MM and PIs to review the incidence of major bleeding. 2) We will also 
continually monitor the study for excessive Day 15 mortality. In parallel with our decision rule related 
to excessive severe hemorrhagic events, we will suspend accrual if we see if we see at least five deaths 
by Day 15 among the first six patients, or at least seven deaths by Day 14 among the first eleven patients. 
If the true Day 14 mortality rate is 70% (which is the historical rate for patients with respiratory 
compromise), the study has a probability of 0.80 of being suspended. Conversely, if the Day 14 mortality 
rate is 50%, the study has a much lower probability of 0.30 of being suspended. 
 
In the event of temporary halt of the study, the PI’s, medical monitor, and independent medical monitor 
will meet to review the data and discuss relatedness to study drugs and determine next necessary steps. 
If the study is halted or terminated, a written statement fully documenting the reasons for study halt or 
termination and subsequent decisions of study execution will be communicated to the IRB and 
appropriate regulatory authorities. 
 
 
 
 
 
14 DATA AND SAFETY MONITORING 
 


 
 
48 
 
The Data Safety and Monitoring Plan (DSMP) will consist of an independent Medical Monitor (a 
physician from UMHS) who will work with the PIs to evaluate AEs. The Investigators and Medical 
Monitors will perform ongoing review of all SAEs in a timely fashion, and regular reviews of all clinical 
data (including AEs and lab data) throughout the study. Any concerns for safety by any of these parties 
will be communicated to the other parties immediately for discussion. The investigators and co-
investigators will meet monthly during the study and will allocate adequate time for such monitoring 
activities.  They will review expected and unexpected adverse events, safety concerns, adherence to 
protocol therapy, study enrollment, and any potential protocol amendments that may be required.  
Recommendations for study continuation, amendments, suspension and/or study termination will be 
made at each of the monthly protocol monitor meetings.    
 
The investigators will also ensure that the monitor or other compliance or quality assurance reviewer is 
given access to all the above noted study- related documents and study related facilities (e.g., pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. If while following 
the Data Safety and Monitoring Plan (DSMP), as outlined in Section 8.5, there is a pattern of unexpected 
and concerning AE or a SAE then, there would be a consideration to create a Data and Safety Monitoring 
Board (DSMB).   
 
 
 
 
 
 
 


 
 
49 
 
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