Safety, Tolerability and Efficacy of Uproleselan (GMI-1271) in Patients With COVID-19 Pneumonia

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Pilot Study to Assess the Safety, Tolerability and Efficacy of Selectin Inhibitor Uproleselan (GMI-1271) in Patients With COVID-19 Pneumonia

Conditions
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COVID-19 Pneumonia

Intervention / Treatment
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* Drug: Uproleselan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Confirmed coronavirus (SARS-CoV-2) (positive real-time reverse transcription polymerase chain reaction test (RT-PCR) for SARS-CoV-2 within 72 hours) enrolled ≤ 48 hours of need for supplemental oxygen. Currently hospitalized requiring supplemental oxygen. 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. Willing and able to participate in all required evaluations and procedures. Exclusion Criteria: In the opinion of at least two investigators, unlikely to survive for >48 hours from screening. Severe chronic respiratory disease (e.g. Chronic obstructive pulmonary disease or other) requiring supplemental oxygen and/or having required mechanical ventilation pre-COVID-19 infection. 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 Currently on invasive mechanical ventilation. Hypotension defined as systolic blood pressure < 90 mmHg on two sequential readings at least 4 hours apart. Total Bilirubin ≤ 3 x upper limit of normal (ULN), Creatinine Clearance ≥ 30 mL/min/1.73m2. Pregnant or breastfeeding. Known diagnosis of an acute thrombosis on admission. 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). Concomitant use of thrombolytic therapy. 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 Venous thromboembolism (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/ History of recent major bleeding, defined in accordance with the criteria of the International Society on Thrombosis and Hemostasis (ISTH). History of bleeding disorder thought to impose excessive bleeding risk as per investigator discretion Hemodynamic instability, defined as inability to maintain mean arterial pressure. Hypersensitivity to the active substance or to any of the excipients of uproleselan. 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a prospective, interventional, single-arm, open label trial, with 1:1 matched de-identified retrospective control cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Uproleselan<br>Uproleselan injection is a sterile solution for IV administration, supplied in single-dose vials at a concentration of 50 mg/mL. | Drug: Uproleselan<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Uproleselan - as Measured by Serious Adverse Events | Descriptive statistics will be calculated for quantitative safety data | Up to 28 days | 
| Safety of Uproleselan- as Measured by Frequency of Serious Adverse Events | Frequency counts will be compiled for classification of qualitative safety data. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Progression to Acute Respiratory Failure for Patients With a Baseline PaO2/FiO2 >= 200 | Patients with a baseline PaO2/FiO2 >= 200: progression of respiratory failure is defined by: severe gas transfer deficit (PaO2/FiO2 < 200); 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. | Enrollment, 15 days | 
| Number of Patients Alive Who Are Free of Respiratory Failure | Number of patients alive and free of acute respiratory failure which required initiation of mechanical ventilation | Up to 28 days | 
| All-cause Mortality | All-cause hospital mortality | Up to 28 days | 
| Time to Change Oxygenation | Number of days it took to reduce their oxygen requirements | during hospitalization; hospital stay ranged from 2 to 10 days | 
| Number of Patients Requiring Mechanical Ventilation | Number of patients requiring mechanical ventilation | Up to 28 days | 
| Change in the World Health Organization (WHO) COVID-19, 8-point Ordinal Scale as Shown by Presenting Selected Time Points Through Day 28 | WHO COVID-19, 8-point ordinal scale has a range of 1-8 with higher numbers indicating a more severe disease. | Enrollment, day 28 | 
| Actual Duration of Hospitalization | Duration of hospitalization - number of inpatient hospital days. Participants were planned to be followed for up to 28 days, although the longest actual hospital stay for a participant was 10 days. | Up to 28 days | 
| Actual Duration of ICU Care | Duration of ICU stay - number of ICU days. Participants were planned to be followed for up to 28 days, although the longest actual hospital stay for a participant was 10 days. | Up to 28 days | 
| Participants Who Experienced Grade 3-4 Hemorrhagic Events | Number of participants who experienced a Grade 3 or Grade 4 hemorrhagic event based on the World Health Organization's (WHO) Bleeding Scale. On the scale, a Grade 3 event means gross blood loss, and a Grade 4 event means debilitating blood loss. | Up to 28 days | 
| Change in E-selectin Plasma Concentrations, as Shown by Values for Each of Those Days | Changes in E-selectin plasma concentrations measured each day for 6 days. | 6 Days | 
| Participants Who Experienced Venous Thromboembolism (Deep Venous Thrombosis or Pulmonary Embolism) | Venous thromboembolism - DVT or PE | Enrollment, up to day 28 | 
| Number of Mechanical Ventilation and Vasopressor Days | Days of mechanical ventilation and days of vasopressors | Up to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uproleselan, Selectin Inhibitor